Evidence-based Review of Drug-Drug, Drug-Natural, and Drug-Food Interactions in the Oncology Setting
Compiled by: Constantine Kaniklidis
Research Director, No Surrender Breast Cancer Foundation (NSBCF)

Drug Interactions in Oncology provides the latest evidence-based critical appraisal of potentially clinically significant pharmacokinetics in breast oncology. [provisional draft pending publication: updated 1 June 2016]

Drug Interactions in Oncology

The Snowbird Tale

Like many others from more Northern climes, a retired man from upstate New York migrates to Florida for the winter (a “snowbird”). Due to high cholesterol and certain other detected elevated cardiovascular risk factors, he is prescribed a statin, atorvastatin (Lipitor). In addition, he adopts a modified lifestyle that includes improved exercise and diet, including generous amounts of fresh citrus, as part of which he elects to consume two or three glasses of fresh grapefruit juice daily. He begins experiencing muscle pain, fatigue and fever, and requires emergency room treatment, where he goes into renal failure and dies, all within the space of 2 months from migration. The fatality, described in detail by Amy Karch, R.N.273, was consequent to co-consumption of grapefruit juice, a known CYP3A4 inhibitor, with atorvastatin, a statin metabolized by CYP3A4 – as are also an estimated over 4000 other prescription medications.


As the label drug interactions warns, concomitant administration of atorvastatin with strong CYP3A4 inhibitors can lead to increases in plasma concentrations of atorvastatin. And the label does carry an explicit warning about grapefruit juice co-consumption but it suggests that adverse interaction is largely secondary to high grapefruit juice consumption, of the order of 1.2 liters (~5 glasses); this is misleading: as in the Karch case, as little as 2 – 3 glasses, and possibly even a single glass (from sporadic case reports), can prove fatal under wide variability of pharmacokinetic parameters. That was shown in another case from the burgeoning arena that has sometimes come to be known as “death by citrus” which includes the fatality of a 29-year old healthy man who consumed just two glasses of grapefruit juice while taking terfenadine (Seldane) antihistamine medication (since 1998, removed from market), inducing fatal cardiac arrhythmias via prolongation in the QT interval, secondary to CYP3A4-mediated ultra-toxic levels of terfenadine198. Regrettably, as in so many cases of adverse pharmacokinetics, no heed was paid to the drug interaction label warning (which we would argue could be less circumspect, and raising the warning to a contraindication, it strikes us, may be more prudent).


The Spectrum of DDIs

This tale highlights the importance of drug-drug, drug-herb, drug-nutraceutical, and drug-food interactions, collectively referred to as DDI (Drug-Drug Interactions) in the expanded sense of “drug” as inclusive of pharmaceutical as well as natural and dietary food agents. As will be seen below, we also have the opposite phenomenon, not of increased serum concentrations, but of clinically significant reduction of drug concentration, as from the case of coadministration of tamoxifen, a CYP2D6-mediated agent, with CYP2D6-inhibitory agents such as certain SSRIs or the GI agent cimetidine (Tagamet), among many others, leading to a decidedly adverse impact on a survival endpoint, inducing a significantly worse time to recurrence (TTR) and disease free survival (DFS) in breast cancer patients252.


Similarly, as we document extensively below, drug-food interactions can be of clinical significance: garlic decreases the levels of antiretroviral (ARV) / protease inhibitor drugs including saquinavir (Invirase) and ritonavir (Norvir), and a seminal garlic–saquinavir interaction study274 found a 51% decrease in saquinavir oral bioavailability consequent to garlic-induced CYP3A4 induction, from as little as two cloves (4 g/each) of garlic.


The Clinician’s Dilemma (and A Solution)

However, it will also be shown below that (1) many preclinical signals raised re potential adverse interactions either may not be of consequence looking at higher human clinical data, and hence lacking in clinical relevance, or that (2) it should not be assumed that such potential adverse interactions necessitate a wholesale prohibition against concurrent administration. Consider the case of resveratrol where preclinical data102 found that it may strongly diminish the susceptibility of MDA-MB-231 cells triple negative breast cancer cells to paclitaxel-induced apoptosis in vitro, and also in vivo. Given that, there are also potential benefits of resveratrol in the oncology context: thus, a recent small randomized controlled double-blind trial275 of the effects of trans-resveratrol in women at increased breast cancer risk observed a decrease in methylation of the tumor suppressor gene RASSF-1α. And we note further that another RCT conducted at the University of Leicester found that micronized resveratrol, compared with tissue from the placebo-treated patients, in patients with hepatic metastases significantly increased in malignant hepatic tissue cleaved caspase-3 by 39%, which is known to be a marker of apoptosis. Albeit preliminary these randomized human clinical data suggest clinically relevant potential benefits. However the potential for adverse diminution of paclitaxel-induced apoptosis remains as we noted102.

We would argue, with that caution in mind, that in fact it is feasible to accommodate synchronous but not simultaneous use of resveratrol and paclitaxel: the half-life of paclitaxel (Taxol) is short, at 5.6 hours, so separating resveratrol consumption by 24 hours on either side of paclitaxel administration evades the problem, given that the half-life of resveratrol itself is only ~9 hours. This strategy, which we have often deployed in clinical context, is a “window of safety” approach that allows synchronous administration without true simultaneous use, enabling potential benefits without triggering significant harms, and in fact uses pharmacokinetics to resolve a problem itself raised by pharmacokinetics.

Another strategy in other contexts may be shift of agent within the same class of drugs as that of some problematic agent. Consider the case of statins: atorvastatin (Lipitor), among several other statins, is a known CYP3A4-inhibitor, entailing significant potential for adverse interaction with other CYP3A4-mediated agents such as the aromatase inhibitor (AI) exemestane (Aromasin). But if comparable lipid control can be obtained, then pravastatin (Pravachol) – or simvastatin (Zocor) or rosuvastatin (Crestor) if needed - can be used in place of atorvastatin (Lipitor), as these are all statins without significant p450-mediated metabolism.

A comparable strategy could be deployed with benzodiazepines most of which exhibit strong CYP3A4 (and some other) metabolic dependencies: in the real-world context, this would suggest substituting lorazepam for the CYP3A4-mediated diazepam, since lorazepam is devoid of clinically significant CYP hepatic enzyme dependencies.


Although molecular mechanisms underlying drug interactions include efflux pump proteins in the ATP-binding cassette (ABC) transporter superfamily, most notably the ABC proteins like P-glycoprotein (P-gp; ABCB1), the vast majority of potential adverse interactions stem from the cytochrome P450 (CYP) family of hepatic enzymes, especially CYP3A4 (over 50% of prescription drugs277, ~7000+), along with in particular the CYP 1A2, 2B6, 2C9, 2C19, and 2D6 enzyme subfamilies, and the cytochrome P450 enzyme family is therefore our focus below.



PATIENT CORNER
Inhibitors | Inducers Substrates


In the world of the (hepatic) Cytochrome P450 system a substrate is a CYP enzyme (technically, isoenzyme) that simply performs a reaction on a medication, an inhibitor is an agent binding so strongly to a CYP enzyme that it prevents the enzyme from metabolizing other medications, while an inducer is an agent that interacts with the enzyme to cause new production of the enzyme.  Thus, an inhibitor of a specific CYP isozyme may decrease the metabolism of the drug and hence increase serum concentrations - and toxicity - of drugs that are substrates for that isoenzyme, while an inducer of a specific CYP isozyme may increase the metabolism of the drug and decrease serum concentrations - and efficacy - of drugs that are substrates for that isozyme.

Anthracyclines and taxanes, as well as the aromatase inhibitor exemestane (Aromasin) and the vinca alkaloid vinorelbine (Navelbine) are predominantly metabolized by the CYP3A4 enzyme, and so we say they are CYP3A4-mediated.  And many other agents are either CYP3A4-inducers and CYP3A4-inhibitors. An
inhibitor will increase the concentration of another agent it's given with (because it inhibits its clearance, and so allows the agent to remain in the system longer than required, increasing toxicity), while an inducer will decrease the concentration of another agent it's given with (because it enhances its clearance, and so allows the agent to remain in the system less time than required, decreasing efficacy). Grapefruit juice is a CYP3A4-inhibitor, and so if consumed with most chemotherapies, will dangerously increase the toxicity of the chemotherapy agent, with hazardous adverse effects and morbidities, and some documented fatalities.

Many natural agents are CYP3A4 inducers or inhibitors and therefore, like grapefruit juice, can either increase the toxicity, or reduce the efficacy, of several chemotherapy agents I noted above, and of the AI exemestane (Aromasin), and these include St. John's Wort, goldenseal, chamomile, sage and licorice teas, and the oils of Evening Primrose and Borage, among others, and so it is prudent to avoid co-consumption during oncotherapy with the agents I noted which are CYP3A4-mediated in their metabolism. Certain statins can also interfere with these same chemotherapy agents, and with the aromatase inhibitor (AI) exemestane (Aromasin).

Another example of adverse interaction concerns tamoxifen metabolism: tamoxifen is predominantly CYP2D6-mediated, and St. John's Wort and all SSRI type antidepressants can interact across the CYP2D6-mediated enzyme to render tamoxifen to near-placebo levels, with obvious and dire consequences, and the clinical relevance, not just in vitro and in vivo, of this was been well established.

The clinical lesson is that extreme caution needs to be exercised to assure that coadministration of agents jointly metabolized across the same cytochrome p450 system enzyme not induce adverse interactions. Avoiding inadvertent compromise of the efficacy and/or safety of the broad spectrum of oncotherapies requires considerable care, and there is therefore unfortunately bound to be a large body of patients whose oncotherapy efficacy may have been compromised not by being refractory to it, or resistant, but rather by then-unknown adverse agent interactions.


Tamoxifen

-- Issues in Tamoxifen Metabolism

Tamoxifen is converted into its active metabolites 4-hydroxy-tamoxifen,
endoxifen, and other active metabolites, in the liver by the CYP2D6 liver enzyme, one of many CYP enzymes that are part of the liver's P450 detoxification pathway (aka the hepatic cytochrome P450 enzyme system), and primarily responsible for the metabolism of tamoxifen into its active metabolites (plasma concentrations of these active metabolites are associated with the cytochrome P450 (CYP) 2D6 genotype). We now know that the efficacy of tamoxifen therapy for the treatment of breast cancer exhibits wide individual variation that appears to be genetic, with some women able to convert tamoxifen into active metabolites more effectively than others; women with the normal gene produce somewhere in the order of two to four times as much of active metabolites as those with the variant that is a relatively ineffective tamoxifen active metabolite converter.

-- Tamoxifen and SSRI Antidepressants

Working from the fact that
SSRI ( selective serotonin reuptake inhibitor) antidepressants are known to be CYP2D6 enzyme inhibitors, Stearns and colleagues1 identified a previously unrecognized active metabolite of tamoxifen, endoxifen, and found that endoxifen was present in substantially higher concentrations than 4-hydroxy-tamoxifen, but after administration of the SSRI antidepressant paroxetine (Paxil) treatment, endoxifen levels decreased, but levels of 4-hydroxy-tamoxifen did not. At that time, the researchers suggested that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen; however, the precise clinical implications of low circulating endoxifen concentrations were not fully2.

Some of the same researchers
3 have revisited this problem, reporting preliminary data from an ongoing prospective study to confirm the original findings. The later study found that certain CYP 2D6 genotypes, as well as the use of the CYP 2D6 inhibitor SSRI antidepressants sertraline and paroxetine strongly influence tamoxifen conversion to endoxifen. However we note that although endoxifen levels were affected adversely, there was no change in concentrations of tamoxifen itself or its other metabolites, thus still leaving unclear the clinical implications of these results (the authors concluded that therefore the findings are still insufficiently powered to dictate any change to prescribing practices at that time).

We further note that although the SSRIs sertraline (Zoloft) and paroxetine (Paxil) as CYP2D6 inhibitors were associated with low concentrations of endoxifen, the dual mechanism agent venlafaxine (Effexor), a serotonin/norepinephrine reuptake inhibitor (SNRI), was not, suggesting that the SNRI venlafaxine (Effexor) in particular may be a potential workaround for breast cancer patients requiring hot flash relief (although we note that gabapentin is also an effective alternative choice; see below our discussion of neuroactive agents). Some confirming evidence of this advantage for venlafaxine was recently put forward by Jin et al. in their prospective observational study4 which found that plasma endoxifen concentration was only slightly decreased by venlafaxine, a weak inhibitor of CYP2D6, but substantially reduced in subjects who took paroxetine (Paxil), a potent inhibitor of CYP2D6), with again the magnitude of the reduction in plasma endoxifen concentration associated with CYP2D6 inhibitor use dependent on the CYP2D6 genotype. The researchers however prudently note that although SSRIs may affect tamoxifen’s antitumoral efficacy or its side effects, this hypothesis requires further testing in actual clinical trials.

-- Tamoxifen and Non-SSRI Antidepressants

Although therefore the SNRI
venlafaxine (Effexor) is a weak CYP2D6 inhibitor, the two other SNRIs mirtazapine (Remeron) and duloxetine (Cymbalta) both appear to have significant potential interaction across CYP2D6 and hence may raise similar adverse interaction potential. 

A systematic review of the literature, as of April 2008, for potentially adverse significant interactions between tamoxifen CYP2D6 metabolism and any antidepressant including SSRIs, SNRIs, tricyclics (TCAs), and various atypicals such as bupropion (Wellbutrin), nefazodone (Serzone), among others, has failed to uncover decisive evidence of any wholly unproblematic antidepressant outside of what is already known solely on venlafaxine (Effexor), and the just FDA-approved venlafaxine analog, desvenlafaxine (Pristiq). However, there are some qualifications to be noted here: 

(1) Mirtazapine (Remeron) at pharmacological concentrations can moderately increase the activity of CYP2D in hepatocytes, with the CYP2D2 isoform being the principle contributor to this effect
5, and the available in vitro and in vivo data suggest that mirtazapine is unlikely to affect the metabolism CYP2D6- metabolized drugs6, and  this having been cross-confirmed and extended to include improbable inhibition of CYP1A2 and CYP3A4 also7. However, there are apparently some discordant findings on CYP2D6: German researchers have found in a small human study that the clearance of CYP2D6 intermediate metabolizers was reduced by 26% compared with that of extensive metabolizers, but we note that this magnitude of decrement is unlikely to be appreciably above borderline clinical significance8. Finally, we should note that the official mirtazapine (Remeron) labeling bares the following warning:

"In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON® with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON® with such drugs."

which we note is in agreement with the conclusions stated by Leon Delbressine and Ria Vos with Organon: "
the contribution of its [mirtazapine] metabolites to the pharmacologic effect is negligible"; "it has no inducing or inhibiting effects on the hepatic P450 enzymes"; "it has a very low potential for clinically relevant pharmacokinetic interactions with other drugs; and its disposition is independent of polymorphic CYP2D6 activity"9

(2) As for the atypical antidepressant bupropion (Wellbutrin), in vitro research has shown that it is primarily metabolized to its major metabolite hydroxybupropion by the CYP2B6 isoenzyme10, and this suggests caution in coadministration with CYP2B6 substrates such as cyclophosphamide (Cytoxan) which is both a CYP2B6 and CYP2C19 substrate11 and accordingly bupropion (Wellbutrin) bares a label warning to this effect, with some caution required also if coadministered with promethazine (Phenergan), among many other CYP2B6 substrates.

And although we note that this is the only CYP enzyme (CYP2B6) noted as a label warning, it appears that there may also be some significant CYP2D6-mediated interactions12,13.  On the one  hand, bupropion product labeling indicates that CYP2D6 is inhibited by bupropion or hydroxybupropion, and on the other the study of Leah Hesse at Tufts and her colleagues14 suggests that at the in vitro level bupropion and hydroxybupropion have relatively low CYP2D6 inhibitory potential, concluding that "bupropion does not inhibit CYP2D6 in vivo and that bupropion itself is not likely to be a substrate for CYP2D6", while on the other we have human volunteer studies such as that of Michael Kotlyar and colleagues (see above) which has suggested a greater potency, at a level of clinically significant adverse interactions and whose study concluded that "Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6". Nonetheless, despite these dissonant findings, the balance of the evidence suggests that bupropion inhibits CYP2D6 and hence may reduce clearance of CYP2D6-metabolized agents, and we consider recent studies as confirmatory of this conclusion, including James Jefferson at the University of Wisconsin and colleagues15 and the recent findings of the GSK team of Melissa Reese and colleagues16 who concluded that the "reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo", and coupled with the human clinical cases cited above, the CYP2D6-inhibitory activity of bupropion (Wellbutrin, Zyban) should be assumed to carry at least a non-trivial potential for significant adverse interactions in humans when coadministered CYP2D6-metabolized agents.     

-- Other Issues re Tamoxifen Pharmacokinetics

More recently still Hiltrud Brauch and colleagues
17 with the German AGO TRAFO Commission further confirmed that recent mechanistic, pharmacologic, and clinical pharmacogenetic evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors, with CYP2D6 being the key enzyme in tamoxifen biotransformation into the clinically relevant metabolites, 4-OH-tamoxifen and endoxifen, influence plasma concentrations of active tamoxifen metabolites and consequently outcome of the patients treated with adjuvant tamoxifen, with non-functional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 variants being associated with higher recurrence rates. This suggests (1) that strong CYP2D6 inhibitors such as SSRI antidepressants should be avoided as co-medication, and (2) that there is an important role for pre-treatment CYP2D6 genotyping to predict metabolizer status and hence outcome, enabling individualization of endocrine treatment choice and benefit. 

In addition, as we note elsewhere in this review, although tamoxifen metabolism is primarily CYP2D6-mediated, there is still a partial non-trivial CYP3A4 dependency.  In this connection, William Chi at Princess Margaret Hospital and colleagues18 have found that a genetic variant of the CYP3A4 gene, CYP3A4*1B, influences endometrial cancer risk: women carrying the CYP3A4*1B allele had 3-fold increase in the risk of developing endometrial cancer from tamoxifen treatment compared with women not on tamoxifen, suggesting that a subgroup of breast cancer patients - namely, CYP3A4*1B allele carriers on tamoxifen - may be at increased risk of developing endometrial cancer.


Aromatase Inhibitors (AIs)

As to the aromatase inhibitors (AIs), there is the potential for drug-drug or drug-herb interactions for all three aromatase inhibitors (AIs), but to significantly different degrees, if there is concomitant medication that interacts with certain cytochrome P450 enzymes.

-- Anastrozole

Anastrozole (Arimidex) inhibits (in decreasing order of magnitude) CYP1A2, CYP2C8/9, and CYP3A4 (as noted by AstraZenica scientists Scott Grimm and Martin Dryoff19. However, although anastrozole (Arimidex) metabolism is in part CYP1A2, CYP2C8/9, and CYP3A4-mediated, and carries an FDA labeling warning to that effect, the FDA has concluded - in the same warning - that these dependencies exist but only at relatively high concentrations in vitro and therefore that it is unlikely that co-administration of a 1-mg dose of Arimidex with other drugs would result in clinically significant drug inhibition in vivo, and as per AstraZenica scientists Scott Grimm and Martin Dyroff's determination, cited above), anastrozole (Arimidex) would not be expected to cause clinically significant interactions with other CYP-metabolized drugs at physiologically relevant concentrations achieved during oncotherapy with anastrozole (Arimidex); we have determined that this is further confirmed by Masha Lam and Robert Ignoffo in their review20.

However, there is known drug-drug interaction of tamoxifen with anastrozole
21 (and with letrozole, see below): concomitant administration of either anastrozole or letrozole with tamoxifen decreases the plasma level of the AI. Anastrozole and tamoxifen administrated concomitantly in the ATAC trial lowered the plasma anastrozole level in the combined arm by 27%.

-- Letrozole

Letrozole (Femara) strongly inhibits CYP2A6, moderately inhibits CYP2C19, and has a low affinity for CYP3A4. This low affinity for CYP3A4 suggests minimal potential for adverse interactions across this enzyme. However, there is a suspicion from the Royal Marsden team that there may be some not wholly resolved or understood adverse pharmacokinetics across CYP2D6 since Mitch Dowsett and colleagues have decisively demonstrated that concomitant administration of letrozole and tamoxifen decreased the level (plasma AUC) of letrozole by 38%22 and given that we know there is only weak affinity of letrozole with CYP3A4, wholly insufficient to explain such a dramatic reduction in letrozole levels (38%), and given that tamoxifen is otherwise only mediated significantly by CYP2D6, the Royal Marsden results raise a caution that some adverse - and clinically significant - interaction across CYP2D6 may yet be activated in a CYP2D6-mediated fashion.   So it should be noted with respect to strong CYP2A6 - and possibly a suspicion also of CYP2D6 - inhibition and moderate CYP2C19 inhibition, in addition to being a CYP3A4 substrate, letrozole (Femara)  bares an FDA label warning to that effect (see also23,24).

-- Exemestane

Exemestane (Aromasin) is metabolized by CYP3A425. And although no drug-drug interactions have been formally reported for exemestane (Aromasin), there remains the potential for interactions with drugs, nutritional agents and herbals that affect CYP3A4.


Fulvestrant

The antiestrogen fulvestrant (Faslodex) has no clinically significant p450 enzyme-mediated interactions.


Lessons Learned re Endocrine Agents

Therefore breast cancer patients undergoing therapy with the following require cautions as indicated:


  1. Taxanes Docetaxel (Taxotere), Paclitaxel (Taxol)), Nab-paclitaxel (Abraxane))
    Note that the paclitaxel-based taxanes - paclitaxel (Taxol) and nab-paclitaxel (Abraxane) - exhibit first-pass extraction by cytochrome P450-dependent metabolic processes, with the CYP2C8 isoenzymes metabolizing paclitaxel to the major metabolite 6-hydroxypaclitaxel the M5 metabolite), and CYP3A4 metabolizing paclitaxel to 3-hydroxypaclitaxel, a minor metabolite (the M4 metabolite)
    26,27,28.  

  2. Vinca alkaloids (vinorelbine (Navelbine), vinblastine (Velban), vincristine (Oncovin)).

  3. Aromatase inhibitor exemestane (Aromasin).

  4. Tamoxifen (mainly CYP2D6-mediated, but potential CYP3A-mediation in addition).

  5. The biological anti-VEGF / antiangiogenic agent bevacizumab (Avastin) undergoes complex biotransformation by different enzymatic routes which includes CYP3A429 (which is reversibly inhibited by bevacizumab (Avastin) and other monoclonal antibodies (MoAbs)).

  6. The biological dual-TKI lapatinib (Tykerb) is a substrate of CYP3A4, CYP3A5 and CYP2D1930. Since lapatinib (Tykerb) is extensively metabolized by cytochrome P450 isoenzyme CYP3A4, concomitant use of strong CYP3A4 inhibitors (including grapefruit juice) can increase lapatinib plasma concentrations and may induced untoward toxicity. If it is necessary to coadminister a strong CYP3A4 inhibitor, pharmacokinetic study data suggest that a dosage reduction to 500 mg/day of lapatinib may adjust AUC (area under the curve) to an appropriate range, and it should be noted that if a strong CYP3A4 inhibitor is discontinued, the FDA advises a washout period of approximately 1 week prior to adjusting the lapatinib dose upwards. In contrast, concomitant use of strong a CYP3A4 inducer (like dexamethasone, carbamazepine, or St. John's Wort, among many others) should be avoided because of the consequent decrease in lapatinib plasma levels. In this case, if coadministration of a strong CYP3A4 inducer is required, lapatinib dosing should be gradually titrated from 1250 to 4500 mg/day based on tolerability, with normal dosing of lapatinib resumed after discontinuation of the CYP3A4 inducer31,32.  


These patients should be cautioned to avoid concurrent use of these CYP3A4-mediated agents: (1) goldenseal and chamomile extracts and teas, (2) St. John's Wort, (3) spices sage, thyme and cloves, (4) soybean components daidzein and genistein, (4) grapefruit juice (via its active component pergamottin), and (5) licorice extracts and teas (via its glabridin active component) to avoid potential and significant modification of the antitumor activity / efficacy, and/or toxicity, of these chemotherapeutic agents; the evidence on potential adverse pharmacokinetics via CYP3A4 with Serenoa repens (Saw palmetto), and EPO (Evening Primrose Oil) / Borage (seed) Oil remains equivocal.


Drug-Herb / Natural Agent Interactions

-- Black Cohosh

The black cohosh extracts can potentially (1) increase the cytotoxicity of doxorubicin and docetaxel and (2) decrease the cytotoxicity of cisplatin, radiation and 4-hydroperoxycyclophosphamide (4-HC), an analog of cyclophosphamide33. In addition, black cohosh has been found to be a potent CYP3A4 inhibitor in vitro34, and this has some grave implications for cancer therapies, given clinical risks associated with changes in either the bioavailability or the metabolic rate of clinically administered drugs. Over 50% of clinically used drugs are oxidized by CYP3A4, which is part of the family of cytochrome P450 (CYP) enzymes responsible for drug metabolism, carcinogenesis (process by which normal cells are transformed into cancer cells) and degradation of xenobiotics (substances foreign to the biological system). However in our critical appraisal of this study we note that this study appears to have used an excessively high dosage of 40 mg of the herbal extract itself, not 40 mg of the herbal drug, the latter being the standard formulation of the Remifemin black cohosh product, and given this, the methodological legitimacy of the conclusions of the widely-cited Tsukamato study are undermined. Indeed, human clinical data has found that black cohosh appears to have no clinically relevant effect on CYP3A activity. The level of CYP3A4 inhibition is estimated at approximately 44% with black cohosh), adversely increasing the bioavailable concentration of drugs metabolized by the CYP3A4 enzyme in the blood (plasma concentrations) via the downregulation suppression of CYP3A4. However, these are strictly in vitro estimates and have been recently shown to be of no clinical significance: Bill Gurley and his coresearchers35 who conducted a human clinical trial assessing the effects of black cohosh (and milk thistle) supplementation on CYP3A activity, finding that black cohosh appears to have no clinically relevant effect on CYP3A activity in vivo (true also of milk thistle). This highlights the importance of at least in vivo confirmation of preliminary in vitro data.

In sum: Concomitant administration of certain dietary / nutritional (including grapefruit, white pepper, and strawberry fruit/Schisandra) and herbal agents is known to affect drug metabolism in humans via inhibiting CYP3A4 activity. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel (Taxotere), paclitaxel (Taxol), etoposide (VePesid, Etopophos, Toposar), irinotecan (Camptosar), ifosfamide (IFEX), imatinib (Gleevec), vinorelbine (Navelbine), vinblastine (Velban), and vincristine (Oncovin).



-- Other Herbals: CYP2D6 and CYP3A4 Activity

Note that the popular herbal goldenseal is also a CYP3A4 inhibitor36 and the same cautions should therefore apply; in addition goldenseal is also, like SSRI antidepressants and St. John's Wort, a CYP2D6 inhibitor and therefore could potentially compromise the antitumor efficacy of chemotherapeutic agents metabolized by this enzyme, the most critical of which is tamoxifen, but also affects the taxane docetaxel (Taxotere). St. John's Wort increases cytochrome P450 3A (CYP3A) activity, but docetaxel is inactivated by CYP3A (on docetaxel pharmacokinetics37, so that the overall consequence seems to be that subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients using St. John's Wort on a chronic basis38. Other CYP3A4 inhibitors include Chamomile extracts and tea39, Serenoa repens (Saw palmetto)40, as well as other herbals and spices such as sage, thyme, cloves, the soybean components daidzein and genistein41, pergamottin (active component of grapefruit juice) and glabridin42 (active component of licorice extracts and teas). 

As to the herbal
valerian, one recent study43 concluded that valerian was the only herb (of 6 studied) that showed a mechanistic inhibition of CYP2D6 activity and that this would therefore suggest caution as to a potential toxicity but as this study was solely an in vitro investigation, it strikes us that the judgment is considerably ahead of the strength of the evidence. And this is supported by the manifestly stronger human clinical trial undertaken by Jennifer Donovan at the Medical University of South Carolina and colleagues44 who found that valerian supplementation at 10.2 mg of valerenic acids daily was associated with a modest increase in alprazolam (Xanax) maximum concentration (Cmax), so typical doses of valerian were unlikely to produce clinically significant effects on the disposition of medications dependent on the CYP2D6 or CYP3A4 pathways of metabolism, and that furthermore the magnitude of the Cmax increase - approximately 20% - was unlikely to be of clinical significance, suggesting therefore that valerian is unlikely to have clinically relevant effects on the disposition of medications that are primarily CYP2D6 or CYP3A4 metabolic pathway dependent. [We note here that recent research45 has clarified that valerian may in fact exhibit pronounced anxiolytic (anti-anxiety), and antidepressant, activity rather than true sedative activity].   Other agents such as silymarin and ginseng, like curcumin, demonstrated no significant CYP3A4 activity. On the other hand, kava kava, like quercetin, and also grapeseed extract (GSE), proved inductive of CYP3A4. Citrus aurantium (Bitter orange), Panax ginseng, milk thistle (silymarin/silybin), and saw palmetto extracts taken by healthy volunteers all had no effect on the activity of CYP3A4, CYP1A2, CYP2E1, and CYP3A4 measured using model substrates46, but in contrast Echinacea exhibits significant effect47. And still other herbal agents such as C aurantium, milk thistle, or saw palmetto extracts appear to pose a minimal risk for CYP-mediated herb-drug interactions in humans46; note that we have here conflicting results for saw palmetto (see Yale & Glulich, above) and it may be that different components are involved, possibly also with component-dose dependencies, much like those seen with St. John's Wort. In addition, it has been demonstrated47 that interactions of Echinacea with anticancer drugs that are substrates of CYP3A4 is likely.


-- St. John's Wort

And note that St. John's Wort is not only a CYP2D6 inhibitor, but also a CYP3A4 inducer
48,49 which may potentially result in lack of therapeutic efficacy of taxanes and Vinca alkaloids, in contrast to black cohosh which is a CYP3A4 inhibitor and so may potentially result in increased bioavailability and plasma concentration of these same drugs, where here the concern would not be loss of therapeutic efficacy but rather adverse increased toxicity. Note that the pharmacokinetics of paclitaxel (Taxotere) is somewhat different from that of docetaxel, undergoing significant metabolism by the CYP2C8 enzyme50. In addition, St. John's Wort has exhibited pharmacokinetic interactions with irinotecan (Camptosar), imatinib (Gleevec), as well as docetaxel (Taxotere), as noted above.

However, we note that St. John's Wort preparations not containing substantial amounts of hyperforin (meaning, under 1%) have not been shown to produce clinically relevant enzyme induction and clinical studies using such low hyperforin preparations have clearly demonstrated the superior antidepressant efficacy over placebo, as well as its equivalence to imipramine (Tofranil, Janimine) and fluoxetine (Prozac) in the treatment of mild to moderate forms of depression. In sum, it would appear that a low-hyperforin preparation (and typically standardized otherwise to 0.3% hypercin) would not exhibit adverse chemotherapeutic interactions if hyperforin content were assured to be less than 1%. On the other hand, the other major component of St. John's Wort, hypercin, does not appear to affect any of the p450 drug metabolizing enzymes, including CYP2D6 and CYP3A4
52. And these findings are borne out by a recent clinical assessment and RCT53 which revealed significant induction of CYP3A4 (approximately 140%) by St. John's Wort.


Melatonin

Melatonin is known to enhance tamoxifen's antitumor activity as evidenced both in preclinical studies and in the seminal human clinical trials of Lissoni. This is possible because SERMs exert their activity not directly but through metabolites across distinct pathways (tamoxifen's antitumor-activity metabolite is endoxifen via the P450 CYP2D6 gene enzyme system, while melatonin's biologically active metabolite is 6-hydroxymelatonin (6-OHMel); indeed it is known that tamoxifen can modulate melatonin biotransformation over the sulfotransferase (SULT) enzyme 1A1 pathway, thus exerting additional antitumor activity. Finally, remember that unlike tamoxifen, melatonin exhibits multiple anti-estrogenic mechanisms besides SERM activity.


Curcumin: The (Putative) "Dark Side", Corrected

Curcumin has been found to inhibit platelet aggregation in vitro54,55,56, and has been found to decrease the aggregation rate in rats57. These findings suggests that curcumin may play the role of a platelet aggregation inhibitor, functioning like clopidogrel (Plavix) but not interfering with it, rather reinforcing and enhancing its fundamental protective activity, leading to the  conclusion that "These results clearly suggest that spice principles [including curcumin] have beneficial effects in modulating human platelet aggregation"58, leading to antithrombotic beneficial effects in cardiovascular atherothrombotic diseases. Note that omega-3 fatty acids (EPA/DHA) as well as EGCG may also have contributory antiplatelet benefit. Therefore, although we lack direct human clinical confirming data,  antiplatelet therapy such clopidogrel (Plavix) dosing may need to be adjusted when there is co-consumption of curcumin, EGCG, or omega-3 fatty acids during active antiplatelet treatment. 

In addition, a number of studies, most recently by Cao et al.59 appear to suggest that high-dose curcumin might induce extensive mitochondrial DNA damage; however, whether this is clinically significant overall is undetermined, and the authors note that such damage might only be an initial event triggering subsequent favorable curcumin-induced apoptosis / cell death. Yet in the aggregate, as Stig Bengmark of the Institute of Hepatology at the London Medical School concluded - and the balance of the evidence shows - from his comprehensive recent review of the medical literature on curcumin60, "Turmeric, an approved food additive, or its component curcumin, has shown surprisingly beneficial effects in experimental studies of acute and chronic diseases characterized by an exaggerated inflammatory reaction. There is ample evidence to support its clinical use, both as a prevention and a treatment". Note: Some curcumin supplements also contain piperine, for the purpose of increasing the bioavailability of curcumin, and piperine may also increase the bioavailability and slow the elimination of a number of drugs, (for example, phenytoin (Dilantin), propranolol (Inderal) and theophylline).


-- Issues with the "Dark Side" Considerations and Findings of Somasundaram and López-Lázaro

In a study of cultured breast cancer cells, curcumin inhibited apoptosis induced by various chemotherapeutic agents campothecin (CPT), mechlorethamine (Mustargen) and doxorubicin (Adriamycin) at concentrations of 1-10 micromoles/liter, as found by Somasundaram and colleagues61 at the Lineberger Comprehensive Cancer Center using an in vivo model of human breast cancer.

But these findings are challenged by the more recent results of Choudhuri et al.62 who observed that curcumin selectively increases p53 expression of carcinoma cells and releases cytochrome c from mitochondria, an essential requirement for apoptosis, leading the authors to conclude that curcumin may have a possible therapeutic potential in breast cancer patients, given the finding of the study that curcumin induces apoptosis in cancer cells sparing normal cells. It is therefore not impossible that curcumin may as the Somasundaram findings suggest inhibit the apoptosis activity of the studied chemotherapy agents, but that either (1) it as Choudhuri has shown provides it's own powerful pro-apoptotic activity, or (2) the overall cytotoxicity and anti-proliferative activity of the chemotherapeutic agents may be unimpaired significantly, as apoptosis is only one of many anti-tumor mechanisms that any oncotherapeutic agent may leverage in its anti-cancer benefit.

Thus, we note that besides the pro-apoptotic activity anti-cancer activity of curcumin, curcumin appears to inhibit cancer cell proliferation by microtubule-inhibition (not unlike the action of the class of taxanes), perturbing microtubule assembly dynamics
63, and in addition curcumin also demonstrates powerful anti-angiogenic activity64. In addition, subtoxic concentrations of curcumin sensitize cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis; TRAIL, also known as Apo2L, is a member of the Tumor Necrosis Family (TNF) family and can induce apoptotic cell death in a variety of cancer cell types, and the activity of curcumin in enhancing TRAIL-mediated apoptosis appears to be an outgrowth of its induction of reactive oxygen species (ROS), generating reactive oxygen intermediates in cancer cells with the associated oxidative stress playing a role as a common mediator of apoptosis65.

In addition, re the Somasundaram findings, these have been taken up and extended by Miguel López-Lázaro and Estefanıa Burgos-Morón and colleagues66 in Seville, Spain, who have coined the term the "dark side" of curcumin for  the set of adverse/negative effects associated with curcumin, and echoed in the reports from Marc Diederich and Marie-Hélène Teiten and colleagues67 in Luxembourg, among others.  It is claimed that by these authors that curcumin blocked, in a dose- and time-dependent fashion, the generation of ROS (reactive oxygen species) which is  otherwise induced by the cyclophosphamide (CTX) and certain other chemotherapeutic agents in MCF-7 (endocrine), MDA-MB-231 (triple negative), and BT-474 (HER2+) human breast cancer cells, and consequentially that such ROS-generation blockade (coupled with blockade of JNK function) thereby prevented breast cancer cells from apoptosis.

However our critical appraisal suggests that there are several fundamental issues raised by these claims that affect their relevancy:


  1. In the Somasundaram findings, the application of curcumin itself did not induce apoptosis, yet in such mammary models curcumin-induced apoptosis is strongly evidenced in the aggregated data to date; thus leaving unclear why in this model, despite the claim of curcumin-inhibited apoptosis of the intrinsic apoptosis expected and systematically manifested in active chemotherapy agent cyclophosphamide, there is no observed pro-apoptotic activity as expected from curcumin itself independent of cyclophosphamide, suggesting a significant methodological problem with and questionable status for this widely cited study. Yet, data shows68 that  curcumin inhibits the AP-1 transcription factor known to be involved in apoptotic program and regulation, also inhibiting the NF-kB transcription factor involved in pro-survival and apoptotic pathways, and recent data has found that curcumin represses histone acetyltransferase-dependent chromatin transcription via inhibition of its p300/CREB-binding protein which plays critical role apoptosis, cell cycle control, differentiation, and other cellular phenomena.  See also below for other findings on curcumin-induced apoptosis contrary to the Somasundaram findings.

  2. Hui Xaio and colleagues69 in China investigated the antiproliferative effect of curcumin combined with cyclophosphamide on the growth of a human lymphoma cell line (HT/CTX) with drug resistance, finding that that the combination of curcumin + CTX had an additional synergistic inhibitory effects on the proliferation and cell cycle distribution of the lymphoma cells, and that curcumin could enhance cyclophosphamide (CTX) toxicity via inhibition of FA/BRCA (Fanconi anemia/BRCA) DNA damage repair pathway, realized by suppression of FANCD2 monoubiquitination, the FA/BRCA pathway known to play a critical role in the cellular response to replicative stress induced by DNA alkylating agents like cyclophosphamide (CTX), thus greatly influencing drug response in cancer therapies. Curcumin + CTX increased the apoptosis inducing effect on the HT/CTX lymphoma cells and in addition effectively reversed multiple drug resistance of HT/CTX cells, this in contrast to either curcumin or CTX alone which was absent any enhanced apoptosis and which moreover was not inhibitory of the FA/BRCA pathway.

    These findings speak directly to curcumin-induced synergistic induction of apoptosis in concurrent administration with cyclophosphamide, in contradistinction to the claimed blockade of cyclophosphamide-driven apoptosis in the dark side findings cited (and it would therefore have to be demonstrated why curcumin + cyclophosphamide would block CTX-induced apoptosis in breast cancer cells but synergistically enhance CTX-induced apoptosis in lymphoma cells.  Comparable claims are made by Somasundaram and López-Lázaro / Burgos-Morón among others of curcumin's interference with the pro-apoptotic activities  of  other chemotherapies such as paclitaxel (Taxol), although we have divergent reports such as those of Srinivas Ganta and colleagues
    70,71 at Northeastern University of curcumin-induced enhancement of paclitaxel efficacy in resistant ovarian cancer cells, enhancing the cytotoxicity in wild-type and resistant cells by promoting the apoptotic response.

  3. López-Lázaro / Burgos-Morón suggest that the negative, “dark side", effects of curcumin are mediated by several mechanisms, including  inactivation of the tumor suppressor protein p53.  But this is equivocal: as noted in Beatrice Bachmeier's recent review72, curcumin can up-regulate the expression of p53 as well as its acetylation, and more directly, Tathagata Choudhuri and colleagues73 have in fact demonstrated curcumin-induced apoptosis in the MCF-7 breast cancer cell line in which expression of wild-type p53 can be induced, with the induced apoptosis accompanied by an increase in p53 level as well as its DNA-binding activity followed by Bax expression at the protein level, showing therefore curcumin induced apoptosis in tumor cells via a p53-dependent pathway in which Bax is the downstream effector of p53, and confirming that p53 signaling acting via Bax activation is essential for the apoptogenic effect of curcumin.  But given that the Somasundaram study tested MCF-7 breast cancer cells, it would therefore be expected that curcumin-induced apoptosis would be observed since Choudhuri used this same cell line with observed curcumin induced apoptosis via a p53-dependent pathway, contrary to the Somasundaram findings and to the claim made by López-Lázaro / Burgos-Morón of curcumin-induced p53 inactivation.  

  4. Another issue concerns what is elided in the Somasundaram and López-Lázaro / Burgos-Morón considerations, namely the well-evidenced pleiotropic activity of curcumin, which has been demonstrated to effect numerous molecular pathways and targets inside the cell, besides just apoptosis, and which we and innumerable other researchers have documented extensively, and which suggests that even if the argument for curcumin inhibition of cyclophosphamide-induced apoptosis were without methodological problems - and our considerations here suggest the contrary - it would nonetheless not follow that the net anticancer effect of curcumin even in a concurrent CTX environment would not be positive, given for example curcumin's well-evidenced angiogenic activity, or its subtle  interference with the micro-RNA system, its transcriptional inhibition of tumor progression, its inhibition of MMP expression, coupled with both anti-invasive and anti-metastatic activities, interference with the inflammatory mechanisms of tumor pathogenesis, potential reversal of multi-drug resistance (MDR)among many others, creating  a complex web of processes influencing multiple major moleclar pathways converging on and promoting carcinogenesis and tumorigenesis and malignant transformation.

  5. There is still another issue at play here in the Somasundaram and López-Lázaro / Burgos-Morón considerations and findings: these, and many others, are based on the assumption that apoptosis is characterized, and its presence detectable, by (oligonucleosomal) DNA degradation. But cell death can occur independently of DNA degradation: curcumin can induce cell death of Jurkat cells despite a simultaneous inhibitory effect on DFF40/CAD endonuclease activity74,75, suggesting that curcumin induces the apoptotic pathway but, at the same time, protects cells against (oligonucleosomal) DNA degradation (apparently inhibiting DFF40/CAD endonuclease activity of without blocking its DNA(17) binding) and further demonstrating that the symptoms of cell death - the apoptogenic signature, as it were - induced by curcumin can be both divergent and also dependent on the cell context, possibly accounting for the apparent discrepancy of evidentiary data on curcumin-based protection against cell death. 

  6. The dark side considerations raised by Somasundaram and López-Lázaro / Burgos-Morón are predicated on the use of traditional curcumin extract, with no posited standardization of the curcuminoid  component, and no bioavailability enhancement.  Yet there are widely used curcuminoid-standardized curcumin formulations such as Sabinsa-certified formulations with piperine (Bioperine) bioavailability enhancement, and curcumin phospholipid complex (CPC) formulations commercially as BCM-95-standardized phospholipid-based curcuminoids, as well as liposomal curcuminoid formulations (commercially, Meriva), as well as several nanoparticle forms, among many others, and these dramatically increased curcuminoid availability.  For example, a human clinical pilot cross-over trial76 conducted by Benny Antony and colleagues in India, of a commercial curcumin-phospholipid complex formulation, BCM-95®CG (Biocurcumax™) which also leverages the synergism between the sesquiterpenoids in the form of turmeric essential oils and the curcuminoids themselves, found that, compared to standard (free) curcumin and to a curcumin-lecithin-piperine formula (comparable to Sabinsa-certified curcuminoids), the relative bioavailability of curcumin-phospholipid complex was 6.93-fold compared to normal curcumin and about 6.3-fold compared to curcumin-lecithin-piperine formula. Furthermore, even if we assume a traditional curcumin extract, the fact as cited by these authors that  no curcumin nor curcumin metabolites were detectable in blood or urine does not foreclose potential antitumor activity; and in a human volunteer trial77 at the  Cytokine Research Laboratory (MD Anderson), brain uptake of curcumin after 2 min was increased by 48% due to coadministration of piperine relative to that with out piperine).  Thus the Ricky Sharma at the University of Leicester and colleagues study78 of curcumin extract in refractory advanced colorectal cancer patients, as well as the Phase II trial from Navneet Dhillon at MD Anderson and colleagues79 of curcumin extract in advanced pancreatic cancer, found evidence of potential benefit. 

  7. This raises a related point, put forth repeatedly by López-Lázaro / Burgos-Morón, that the concentrations of curcumin and its metabolites achievable outside the gastrointestinal tract by oral extract consumption are simply insufficient to provide significant antitumor activity, citing that "the plasma concentrations of curcumin in people taking relatively high oral doses of curcumin are very low, typically in the nanomolar range. This means that the oral administration of curcumin does not lead to cytotoxic concentrations outside the gastrointestinal tract". This is a familiar charge, made also in connection with the curcumin dosing in pancreatic cancer study, namely that the biological activities observed are  less likely to be due to curcumin, given that the serum levels observed are only in low nanogram range (in that study curcumin was coadministered with gemcitabine (Gemzar)). But  there is reason to believe that serum levels of curcumin observable in vivo in human patients cannot be directly compared with those in vitro in the cell culture medium, in part understandable when we appreciate that exposure of cells to curcumin in cell culture models/experiments is generally only short-term, rarely above 24 -72 hours, as opposed to the standard long-term exposure of even up to 6 months in humans, and more critically, curcumin cell/tissue levels rather than serum/cell culture levels are more relevant.  So in the above cited Sharma colorectal cancer study, even though the concentration of 3600 mg/d curcumin in normal colorectal tissue was 12.7 +/- 5.7 and in malignant colorectal tissue 7.7 +/- 1.8 nmol/g, these low doses had pharmacological activity in colorectum as measured by effects on levels of M(1)G and COX-2 protein80.  Thus curcumin pharmacokinetics observed in tissues after i.p. administration cannot be compared directly with those observed after gavage or dietary intake81.



-- Conclusions

Despite our criticisms of the dark side perspective presented above and our judgment for reasons specified that  the claims are, in the face of the aggregated cumulative evidentiary base, unconvincing and the divers claims put forth not sufficiently robustly demonstrated, exhibiting as they do the serious methodological flaws we have discussed here, nonetheless Somasundaram and López-Lázaro / Burgos-Morón (and to a lesser  extend Diederich/Teiten via favorable citation) are to be commended in raising  awareness of the often overlooked consideration that for any oncotherapeutic agent whether traditional or CAM-based, the deployment decision always involves a weighing of the benefit/harm ratio and that clinicians should therefore obliged themselves to master the relevant body of data on the issue of the benefit/harm ratio to permit an open-minded, candid, and informed discussion with the patient in determining, in consultation, the best  choice  relative of course to the context (where patients in more advanced disease settings may accept a higher degree of risk of potential harm or adverse interaction than those in earlier stage disease). That said, the overwhelming balance of the evidence to date continues to support the safety and efficacy of various curcuminoid preparations as adjunct oncotherapeutic agents.


-- Curcumin and the P450 Cytochrome System: What We Know

Curcumin is a known powerful inhibitor of the carcinogen-activating enzymes CYP1A1, CYP1A2, and CYP2B2, which like other inhibitors of these isoenzymes, forms part of its basis of favorable activity in the inactivation of carcinogens (such as tobacco carcinogens82. Curcumin is also one of several flavonoids, in addition to quercetin, resveratrol and apigenin that were investigated for their ability to induce CYP3A4 in human hepatocytes, but it was determined that only quercetin produced accumulation of CYP3A4 mRNA, as demonstrated by Judy Raucy of the California Toxicology Research Institute / CTRI83, so curcumin appears to lack significant CYP3A4 activity.

Despite the lack of CYP3A4 induction as demonstrated by the above-cited findings of Judy Raucy at CTRI and others, some authors84,85 have continued to raise concern about curcumin's theoretical potential for adverse hepatic-enzyme mediated interactions.  In this connection, it is critical to differentiate between the Curmunas which are represented by C. longa, C. aromatica and other Curcumas except for C. zedoaria, versus curcumin as the phenolic compound isolated from the rhizomes of Curcumas, since Xiao-Long Hou and colleagues86 at Osaka University demonstrated that curcumin as opposed to Curcumas regulate the function of P-gp in completely opposite ways; similarly, as to effects over the cytochrome p450 cytochrome system, the same team concluded that "both Curcuma extracts and curcumin treatment had no influence on CYP3A4 mRNA expression" and that curcumin was not the major compound responsible for putative enzyme inhibitory effects87.

Furthermore, Regina Appiah-Opong and colleagues
88 at the Leiden/Amsterdam Center for Drug Research (LACDR) evaluated the potential hepatic enzyme interactions of curcumin decomposition products, concluding that "In spite of the significant inhibitory activities shown towards the major CYPs in vitro, ... given the reported low systemic exposure of the liver to curcumin . . . The decomposition products of curcumin showed no significant inhibitory activities towards the CYPs investigated, and therefore, are not likely to cause drug–drug interactions at the level of CYPs”.  Therefore, we conclude, in agreement with these and other findings, that the weight of the evidence suggests that clinically relevant DDIs involving curcumin, and in particular curcuminoids (as opposed to raw Curcumas) are improbable and that the evidence base is devoid of any clinical data of significant DDI interactions exerted by curcumin / curcuminoids. 
    


Resveratrol

As to resveratrol, it selectively suppresses the transcriptional activation of cytochrome CYP1A189, also inhibiting COX-1 and COX-2 enzymatic activity, and also suppressing the induction of the oncogenic NF-kB transcription factor, with antiproliferative, proapoptotic, and antiaromatase activity. Indeed, its well-evidence antitumor activity is based in part on its inhibition of both the constitutive and the induced expression of CYP1A1 and CYP1B1, commonly overexpressed in breast and many other cancers, in a dose-dependent manner90-95, while its specifically anti-aromatase activity is due to the enzyme-level inhibition of the CYP19 aromatase enzyme and possibly also by decreasing mRNA CYP19  expression at the transcription level96-98.  

-- Resveratrol, CYP19, Aromatase, and Estrogenicity

With respect to resveratrol, it should be noted that Barry Gehm and colleagues
99 at Northwestern first suggested that resveratrol exhibits variable degrees of estrogen receptor agonism in different test systems, and may have estrogenic activity in vitro, but the later in vivo results from Russell Turner's team at Mayo100 found, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist, and this lack of estrogenic activity of resveratrol has been cross-confirmed by Martina Böttner at the University of Lübeck and colleagues101, and by Krishna Bhat and colleagues102 at the University of Illinois who found in vivo evidence of resveratrol acting as a chemopreventive SERM. Furthermore, Yu Wang and colleagues103 at The Chinese University of Hong Kong established that resveratrol inhibited the enzyme activities and reduced the mRNA abundance of CYP19, thus functioning as a bilevel inhibitor of aromatase, reducing localized estrogen production in breast cancer cells. And most recently, Alois Jungbauer's team104 in Austria found that only 2% of the estrogenic activity of red wines was due to trans-resveratrol, thus suggesting that the estrogenicity of red wines is not due to resveratrol, but rather to the wine flavonoid kaempferol.


-- Caution - Resveratrol and Paclitaxel

A recent preclinical study of resveratrol from Masuyuki Fukui and colleagues105 at the University of Kansas found that that resveratrol strongly diminished the susceptibility of certain breast cancer cells, including triple negative (MDA-MB-231 cells)" to paclitaxel-induced cell death in culture, and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied).

-- Other Considerations

Similarly, boswellic acids, derived from the Boswellia (frankincense) species do not appear to exhibit any significant CYP-mediated dependencies106

However (see more below), phenytoin (Dilantin), mifepristone (Mifeprex), omeprazole (Prilosec), clotrimazole (Lotrimin), lovastatin (Mevacor), atorvastatin (Lipitor) and mevastatin (Compactin) were all capable of enhancing the expression of hepatocyte CYP3A4 mRNA.


EGCG and Green Tea Extracts and Components

Issues of Safety and Interaction
Sherry Crow and colleagues107 at the Arizona Cancer Center observed that preclinical studies suggested that green tea or green tea catechins can modulate the activities of drug-metabolizing enzymes, and they conducted a clinical study to determine the effect of repeated green tea catechin administration on human cytochrome P450 (CYP) enzyme activities, finding that repeated green tea catechin administration (at a dose that contains 800 mg epigallocatechin gallate (EGCG) daily) is not likely to result in clinically significant interference with the disposition of drugs metabolized by CYP enzymes (CYP1A2, CYP2D6, CYP2C9, and CYP3A4).

Synergy with Chemotherapy and Reversal of Drug Resistance
Yuying Mei et al.
108 explored the reversal effects on multidrug resistance (MDR) via the antioxidant capacities of tea polyphenols, and EGCG in particular, based on the observation that drug resistance cells undergo oxidative stress, confirmed in doxorubicin (Adriamycin)-induced intracellular concentration of ROS (reactive oxygen species), and this MDR was reversed by tea polyphenols and EGCG. This was confirmed in the study by Feng Qian and colleagues109 at the East China University of Science and Technology who investigated the molecular mechanism of EGCG and its activity in the reversal of P-glycoprotein (P-gp) mediated MDR (multidrug resistance), finding that in vitro EGCG potentiated the cytotoxicity of doxorubicin to drug-resistant KB-A1 cells, and that in a KB-A1 cell xenograft model, EGCG addition enhanced the efficacy of doxorubicin, increasing the concentration of doxorubicin in resistant tumors, suggesting that EGCG modulates the function of P-gp and reverses P-gp mediated multidrug resistance in human cancer cells. And these findings themselves further confirm the earlier in vivo results of Qiang Zhang and colleagues110 who found that EGCG increased by 51% the concentration of doxorubicin in resistant tumors and also increased doxorubicin-induced apoptosis in those tumors, with the doxorubicin/EGCG combination being well-tolerated, and concluded therefore that EGCG chemosensitizes resistant tumor cells to doxorubicin.

Similar results were established in animal studies of leukemia, with doxorubicin-resistant leukemia cells (P388) by Yasuyuki Sadzuki and colleagues
111 at the University of Shizuoka Japan, who found that green tea components (including caffeine, theanine, and EGCG) increased the doxorubicin-induced efficacy against these cells via an increase in the doxorubicin concentrations in the tumors and hence increasing the doxorubicin-induced antitumor activity. These results were confirmed and extended in the research of the Mayo Clinic team of Yean Lee and colleagues112 who observed that it has been previously established that CLL (chronic lymphocytic leukemia) cells synthesize and release VEGF (vascular endothelial growth factor) under normoxic and hypoxic conditions, and that CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2) which are spontaneously phosphorylated on these cells, suggesting that these cells are using VEGF as a survival factor, given that VEGF significantly increases the apoptotic resistance of CLL B cells. They therefore evaluated the impact of EGCG (epigallocatechin-3-gallate), a known receptor tyrosine kinase (RTK) inhibitor, on the VEGF receptor status and viability of CLL B cells, finding that EGCG significantly increased apoptosis/cell death in 8 of 10 CLL cell samples and suppressed both the Bcl-2 (B-cell leukemia/lymphoma-2), XIAP (X-linked inhibitor of apoptosis protein), and Mcl-1 (myeloid cell leukemia-1) proteins in the CLL cells, as well as VEGF-R1 and VEGF-R2 phosphorylation (incomplete suppression); they concluded from these findings that VEGF signaling regulates CLL cell survival signals and that interruption by EGCG of this autocrine pathway results in caspase activation and subsequent leukemic cell.

And more recently TD Shanafelt and colleagues
113 at the Mayo Clinic (Rochester, MN) confirmed the ability of EGCG to induce apoptotic cell death in the leukemic B-cells in patients with CLL (chronic lymphocytic leukemia (CLL)). Indeed, the researchers document several patients with low grade B-cell malignancies seen in clinical practice at the clinic with steady clinical, laboratory, and/or radiographic evidence of progression who on their own initiative, began EGCG consumption and subsequently developed objective clinical response. Moreover, Tae Heung Kang and Chinese and Korean colleagues114 and researchers at Johns Hopkins found that a multimodality treatment regimen using DNA vaccination in combination with EGCG was effective in inhibiting large tumor growth, inducing tumor cellular apoptosis in a dose-dependent manner and enhanced tumor-specific T-cell immune response and enhanced antitumor effects, resulting in a higher cure rate than either immunotherapy or EGCG alone, as well as providing long-term antitumor protection in cured mice.


Some Common Drug-Drug Interactions


Statins and Oncotherapy

Atorvastatin (Lipitor) is another drug metabolized over the p450 cytochrome pathway and used by many breast cancer patients, and is known to be a potent CYP3A4-inhibitor, entailing significant potential for adverse interaction with other agents dependent on CYP3A4-mediated metabolism. One such, as we discussed above, is the aromatase inhibitor (AI) exemestane (Aromasin), but there are many others: restricting my attention to those with known clinically relevant interactions, these are:


Erythromycin (antibiotic),
Benzodiazepines (anti-anxiety agents),
Chlorpheniramine (Chlortrimeton, an antihistamine),
Calcium channel blockers (for cardiovascular disorders),
Tamoxifen (tamoxifen has extremely subtle and complex pharmacokinetics and pharmacodynamics) and
Vincristine (Oncovin], and
Grapefruit juice, which is one of the most powerful CYP3A4-inhibitors ever discovered (with even many recorded fatal interactions).


One workaround is to explore switching to simvastatin (Zocor) or pravastatin (Pravachol), two statins without significant p450-mediated metabolism.  Another option is rosuvastatin (Crestor), the newest and most potent of the FDA approved statins; it has been established that rosuvastatin is not extensively metabolized by  cytochrome P450 isoenzymes, and so and inhibitors of these isoenzymes do not  affect it in clinically significant ways, and although it is minimally - and clinically insignificantly - metabolized in the CYP2C9 isoenzyme pathway and to lesser extent in the CYP2C19 isoenzyme pathway,  It is not metabolized by means of cytochrome P450 (CYP) 3A4, and furthermore rosuvastatin does not have any inhibitory or inducing effects on the cytochrome P450 hepatic enzyme system.

It should be noted that several studies have raised some safety issues concerning statins including rosuvastatin, most notably the postmarketing analysis of Alawi Alsheikh-Ali and collegaues116,117 at Tufts which reviewed statin-associated events reported to the FDA during rosuvastatin’s first year on the market. The adverse event reports for rhabdomyolysis, proteinuria, nephropathy, or renal failure were higher for rosuvastatin than for atorvastatin (Lipitor), simvastatin (Zocor), or pravastatin (Pravachol). In answer to a petition filed with the FDA by Health Research Group of Public Citizen, the FDA acknowledged that postmarketing rosuvastatin kinetics studies found that Asian Americans experience blood levels of the drug twice as high as non-Asians, potentially predisposing to severe myopathy, and for that reason, the FDA advises that rosuvastatin be used only in low doses in Asian Americans, although Scott Grundy118 with the Center for Human Nutrition, and others119,120 in the same vane, provides some prudent perspective on these safety issues. See also the recent cautious and provocative assessment by Mark Golstein of statins and cancer risk, and  the sobering conclusion that "there is ample evidence that statins may promote cancer in certain segments of the population. Currently, the indications for statin therapy are based on lipoprotein levels, prevalent cardiovascular disease, other vascular risk factors, and family history. Maybe it is time for a new paradigm that also includes age extremes, prevalent cancer, a past history of cancer, and overall immunocompetence"121


Antisecretory (PPI and H2RA)

PPIs (proton pump inhibitors) including omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), and esomeprazole (Nexium), and most H2RAs (histamine-2 receptor antagonists) including cimetidine (Tagamet), famotidine (Pepcid), and nizatidine (Axid) have CYP2C19-mediated hepatic metabolism and so represent potential adverse interaction with letrozole (Femara) which is also CYP2C19-dependent in part for its activity. The PPI rabeprazole (Aciphex) is mainly metabolized via a non-enzymatic pathway to thioether-rabeprazole, with relatively small CYP2C19 involvement; however even with rabeprazole (Aciphex) there is some theoretical potential for CYP2C19-mediated interaction, although this appears much less so than with any of the other PPIs.  Of the H2RAs, ranitidine (Zantac) is considered a weak CYP2C19 inhibitor and so may be safer than others in coadministration with letrozole (Femara), but Slobodan Rendic's review124 notes that "Although the results obtained with ranitidine showed a low inhibitory potential, drug-drug interactions were reported in some cases", and the same review suggests that famotidine (Pepcid) and nizatidine (Axid) also possess "a weak cytochrome P450 inhibitory potential and a low drug-drug interaction potential", while cimetidine (Tagamet) "is a strong inhibitor of the CYP2D6 and 2C19 enzymes in vivo". Thus with respect to the H2RAs, the best we can conclude on the evidence is that cimetidine (Tagamet) appears to exhibit the greatest potential for adverse drug interactions across especially the CYP2D6 and CYP2C19 enzymes, while ranitidine (Zantac) appears to be a weak CYP2C19-inhibitor,as do famotidine (Pepcid) and nizatidine (Axid) although there is nonetheless some residual small possibility for adverse drug interactions with all agents, especially cimetidine (Tagamet)122-129.    


Muscle Relaxants

Metaxalone (Skelaxin) - like most muscle relaxants (carisoprodol (Soma, Rela), cyclobenzaprine (Flexeril), orphenadrine (Norflex, Norgesic), and chlorzoxazone (Parafon) - has CYP3A4-dependent metabolism, although two - tizanidine (Zanaflex) and methocarbamol (Robaxin) - are exceptions and could be used as safe alternatives; however, tizanidine (Zanaflex) is mainly CYP1A2-dependent130, while methocarbamol is metabolized via dealkylation and hydroxylation [Methocarbamol Package Insert - Pharmacokinetics].  Phenyltoloxamine (Novagesic, Dologesic, Flextra, Phenylgesic) when combined as it typically is with acetaminophen (Tylenol) however is a weak CYP3A4 inhibitor, although a moderate CYP2D6 inhibitor, although the contribution of moderate CYP2D6 inhibitor and weak CYP3A4 inhibitor activity appears to be essentially from the acetaminophen131,132.


Benzodiazepines

As to sedative / hypnotics in the class of benzodiazepines - such as alprazolam (Xanax), chlordiazepoxide (Librium), clonazepam (Klonopin), clorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), midazolam (Versed), oxazepam (Serax), temezepam (Restoril), and triazolam (Halcion) - the safest from this drug interaction standpoint are temezepam (Restoril) and lorazepam (Ativan), as these are not significantly metabolized at all by the P450 cytochrome system of hepatic enzymes (both temezepam and lorazepam directly undergo glucuronide conjugation), and so can typically be used concurrently with other agents, including oncotherapeutic ones, without interaction issues
133, and oxazepam (Serax) may also be relatively free of hepatic enzymes interactions, as it - like lorazepam (Ativan) - is not oxidatively metabolized by cytochrome P450 but rather  glucuronidated by glucuronyl transferase134. Note also that in addition to being a CYP3A4 substrate as are most benzodiazepines, diazepam (Valium) has additional dependencies over CYP1A2, CYP2C8/9, and CYP2C19135.  

What of non-benzodiazepines such as zolpidem (Ambien), Zopiclone (Lunesta), Zalephon (Sonata) and ramelteon (Rozerem)? In contrast to most (but not all - see above) benzodiazepines, these newer hypnosedatives are biotransformed by multiple CYP isozymes in addition to CYP3A4, so that CYP3A4 inhibitors and inducers would tend to have a lesser effect in the aggregate on their biotransformation
136. And Zolpidem (Ambien) even at extremely high dosing levels of approximately 200 times maximum therapeutic concentrations produced negligible or weak inhibition of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A, and is highly unlikely to induce clinical drug interactions across hepatic CYP enzymes P-gp mediated transport137,138. As to ramelteon (Rozerem), a melatonergic (melatonin receptor) agonist, the major isozyme involved in its metabolism is CYP1A2, with the CYP2C subfamily and CYP3A4 isozymes also involved to a minor degree139,140.  One caution however is coadministration of rameleon (Rozerem) with a strong CYP3A4 inhibitor (such as erythromycin, clarithromycin, ketoconazole, itraconazole, telithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole, and grapefruit juice) requires caution141.  


Selective Non-Narcotic Pain Relievers
-- Acetaminophen (Tylenol)
As noted above,
acetaminophen (Tylenol) is a weak CYP3A4 inhibitor and a moderate CYP2D6 inhibitor. But a finer appreciation of acetaminophen's pharmacokinetics strongly establishes that these cytochrome P4540 hepatic enzymes pathways are of no clinical significance: acetaminophen is metabolized in the liver by two distinct pathways, 85% to 90% of a dose being conjugation with activated sulfate and glucuronic acid via a phase II reaction, with a small proportion of metabolized by a phase I cytochrome P450 (CYP) reaction to a reactive, electrophilic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI). And most critically, recent human clinical data have clarified that only the CYP2E1 isoenzyme plays any significant role in acetaminophen's cytochrome P450 metabolic pathway, via the reactive intermediary metabolite NAPQI, and that the contributions of other cytochrome p450 isozymes of cytochrome P450 appear to be negligible142, and hence the interaction of acetaminophen with other agents over non-CYP2E1 hepatic enzyme pathways is likely to be clinically insignificant143, and we observe further that the contribution of the CYP3A4 pathway to total NAPQI formation varies from 1% to at most 20%144,145,146.  Note further that only a small percentage of acetaminophen is converted to the NAPQI metabolite, normally detoxified by hepatic glutathione (GSH), which accounts in part for acetaminophen-induced hepatic injury under certain circumstances, such damage not being secondary to the drug (acetaminophen) itself but rather to the NAPQI metabolite147,148,149.

-- Celecoxib (Celebrex)
Although no published studies have yet evaluated the impact of
celecoxib (Celebrex) on CYP-metabolized drugs, it did not effect CYP2C9-metabolized drugs (such as warfarin, a substrate) in vivo. However celecoxib (Celebrex)  inhibits CYP2D6 and so may increase serum concentrations of CYP2D6 substrates, including many SSRI and tricyclic antidepressants, antifungals, antipsychotics, narcotic analgesics such as codeine, and ß-blockers150.  But in balance, we note that there is some reassurance from the fact that no safety signals concerning adverse interaction with AI therapy have been to date raised to date from the CAAN Trial, the NCI-based letrozole-Celecoxib Trial, and the UK-based NEO-EXCEL Trial, all combining aromatase inhibitors with concurrent celecoxib (Celebrex).

-- Other Analgesics
Diclofenac (Voltaren, Voltaren Gel) is predominantly metabolized by CYP2C9151, and naproxen (Naprosyn, Aleve) by CYP2C9 and CYP1A2152, while tramadol (Ultram/Ultracet) CYP2D6 is primarily responsible for M1 (O-desmethyl-tramadol) formation, with M2 (N-desmethyl-tramadol) formation catalyzed by CYP2B6 and CYP3A4, these being the two primary tramadol metabolites153.


Anti-Allergy Agents

Diphenhydramine is a CYP2D6 and CYP3A4 inhibitor , it is for that reason problematic with letrozole (Femara) - which is also partially metabolized by the hepatic CYP2D6 and CYP3A4 enzymes - as to potential adverse interaction and may interfere with letrozole activity (and note that the official product labeling of letrozole (Femara) carries a warning about this potential adverse interaction from coadministration with diphenhydramine (Benadryl))
154,155.

Montelukast (Singulair):  The leukotriene receptor antagonist montelukast (Singulair) exhibits weak but noninhibitory activity on CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP3A4-catalyzed reactions156, with some comparatively weak induction of significant CYP2C9 inhibition in vitro, although it does not affect the pharmacokinetics of the CYP2C9 S-warfarin substrate, and does not in addition inhibit CYP2C8-mediated metabolism and so behaves as a selective CYP2C8 inhibitor, and therefore in the  aggregate is  considered a safe agent without significant drug-drug interactions (DDIs)157.

Budesonide is a corticosteroid, found in micronized form, along the selective beta2 agonist, formoterol fumarate dihydrate, in Symbicort, and also in other inhaler form allergy / asthma medications such as Rhinocort and Pulmicort,and also for treatment of Crohn's Disease under the Entocort label.  It is predominantly metabolized by the  CYP3A4 isoenzyme
158-161.  The antihistamine cetirizine (Zyrtec) appears to not exhibit adverse hepatic cytochrome p450 mediated interactions 162.


Antiplatelets

Antiplatelet agents such as - aspirin, clopidogrel (Plavix), dipyridamole (Persantine), and ticlopidine (Ticlid) - exhibit some significant cytochrome P450 hepatic enzyme dependencies, typically CYP2C19- and CYP3A4-mediated. Clopidogrel (Plavix) appears to be mainly CYP2C19-dependent metabolically163,164, as is low-dose aspirin165, both of which also appear to have some CYP3A4 dependencies166,167.  And both clopidogrel (Plavix) and ticlopidine (Ticlid) are also CYP2B6 inhibitors168, while clopidogrel (Plavix) is also a CYP2C9 inhibitor169,170

With respect to clopidogrel (Plavix) it should also be noted that the OCLA (Omeprazole CLopidogrel Aspirin) Study that omeprazole (Prilosec) significantly decreased certain clopidogrel platelet inhibitory effect
171,172, although the precise clinical significance of this has not been as yet fully clarified. Finally, ticlopidine (Ticlid) is selective for CYP2C19173, and CYP2B6174.


Thyroid Agents

Levothyroxine (Synthroid): levothyroxine (Synthroid) does not appear to be a substrate for any major drug metabolizing CYP-enzyme175.


Vitamin D3 (Cholecalciferol)

Cholecalciferol (Vitamin D3) itself does not appear to have any significant biological activity, but rather the principal circulating form of vitamin D3 is 25-hydroxyvitamin D (also referenced as 25-hydroxycholecalciferol), or 25(OH)D for short, another reference for calcidiol, which is activated by renal 1 α-hydroxylase (also know as the enzyme vitamin D-25-hydroxylase) to form the metabolically active form of vitamin D3, 1,25-dihydroxvitamin D (1,25(OH)2D), aka calcitriol. Thus there is a two-phase hydroxylation of cholecalciferol: (1) in the liver to 25-hydroxycholecalciferol [25(OH)D3] and then (2) in the kidney to 1,25-dihydroxycholecalciferol (1,25(OH)2D) – calcitriol, and this (calcitriol) being the active form of vitamin D3 which exerts its effects by directly binding to the vitamin D receptor (VDR)176,177,178. It is the mitochondrial enzyme CYP27B1 that catalyzes 1-hydroxylation in the kidney, and in addition CYP2R1 appears to be the biologically relevant vitamin D 25-hydroxylase179, with another hepatic enzyme CYP24A1 (known as 25-hydroxyvitamin D-24-hydroxylase) regulating the concentrations of both the precursor 25(OH)D and the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, and hence playing an important role is vitamin D homeostasis180,181.

Warning: The
NCI Cancer Therapy Evaluation Program (CTEP) - uniquely, against all  other authoritative sources - lists cholecalciferol (Vitamin D3) as a CYP2C19 inhibitor in their “Cytochrome P450 Drug Interaction: Tables List of drugs that may have potential CYP2C19 interactions (Appendix C; Word .doc file)”182.  This is in error and devoid of methodologically robust evidentiary support, and indeed appears medically misreasoned since, as noted above, cholecalciferol is a precursor and itself has no significant biological activity, and so the important pharmacokinetics are those of 25(OH)D (25-hydroxyvitamin D / 25-hydroxycholecalciferol), aka calcidiol, and the metabolically active form of vitamin D3, 1,25(OH)2D (technically, 1,25-dihydroxvitamin D, aka calcitriol, and it is established that these are mediated by CYP27B1, CYP24A1, and CYP2R1, and so any hepatic enzyme dependency of the precursor agent cholecalciferol (Vitamin D3) itself is clinically of no significant consequence or relevance.

Our review of this issue suggests that the authority of the NCI CTEP inclusion appears to be a single early study
183; the clinical relevance of this isolated, and never to date cross-confirmed or validated, study investigating the effects of a number of agents including cholecalciferol on xenobiotic oxidations catalyzed by 12 recombinant human cytochrome P450 enzymes and by human liver microsomes is unclear and has not been to date established, and cannot stand against the weight of the evidence base.  And indeed our own review has revealed that this aberrant finding is directly refuted by an independent team under Shin-ichi Kamachi184 with BCG-Japan: fourteen P450 isoenzymes (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2D6-Met, 2E1, 3A4, 4A11) were tested for their 25-hydroxylation activity of 1-OH-D3, and it was concluded that (1) none catalyzed the 25-hydroxylation reaction, and that (2) the 25-hydroxylation activity of 1-OH-D3 localized in the microsomal fraction appears to be attributable to a cytochrome P450 other than those tested in this study.  Of course, unknown to the investigators at that time (2001) later research which we reviewed and cited above has established the critical dependencies to be those of the CYP27B1, CYP24A1, and CYP2R1 isoenzymes, not on CYP2C19, CYP2D6 or CYP3A4 among others.        


Beta Blockers

Of the several beta-adrenergic blocking agents -
propanolol (Inderal), atenolol (Tenormin) timolol (Blocadren), carvedilol (Coreg), and labetolol (Normodyne, Trandate) - metoprolol (Lopressor, Toprol) is the classic CYP2D6 substrate, almost universally used as the model substrate for this hepatic enzyme although all these beta blockers are CYP2D6 substrates to different degrees. Among the β-blockers, metoprolol is most highly CYP2D6-dependent (70 - 80% metabolized over CYP2D6 pathway)185,186,187
 


Food-Drug Interactions

It is now recognized that there are many potentially clinically significant food-drug interactions
188, since drug-food, drug-herb or drug-drug interactions can occur when any orally administered CYP3A substrate is given concomitantly with an inhibitor or inducer of intestinal CYP activity189, and potentially adverse interactions have been raised in hundreds of studies.  To take one of dozens of examples, several studies have shown that broccoli increases CYP3A activity190-193, and hence can adversely interact with a broad range of CYP3A4-mediated oncotherapies, including as documented above, taxanes (docetaxel (Taxotere), paclitaxel (Taxol)), vinca alkaloids (vinorelbine (Navelbine), vinblastine (Velban), vincristine (Oncovin)), and aromatase inhibitors, all CYP3A4-mediated, as well as tamoxifen which although mainly CYP2D6-mediated, exhibits potential CYP3A-mediation in addition. So, for example, the aromatase inhibitor exemestane (Aromasin) which is extensively metabolized by CYP3A4, carries an FDA label warning that "co-medications that induce CYP3A4 may significantly decrease exposure to exemestane"; similarly for vinorelbine (Navelbine) which carries the FDA label warning that "caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily", with comparable warnings for docetaxel "the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4", and the other hormonal and chemotherapeutic agents we identified above as CYP3A4-mediated in their metabolism194.

In addition to increasing CYP3A(4) activity as documented immediately above, broccoli -  like all brassica vegetables - also increases CYP1A2 activity in humans
195, an adverse interaction since increased CYP1A2 function is associated with increased risk for breast cancer196, confirmed independently by the demonstration that CYP1A2 activity in postmenopausal women was positively associated with mammographic density197. Thus, food components like those of brassica / cruciferous vegetables may exhibit potentially adverse activities along multiple CYP pathways: both over the p450 cytochrome hepatic enzyme system via CYP-mediated interactions with concurrent oncotherapies, as well as independently of any coadministration with oncotherapy, via adverse increase of (among others) CYP1A2 activity which is established as directly elevating breast cancer risk. In both cases the adverse impact is mediate by p450  CYP enzymes, but only the first is interactive with concurrent oncotherapy, the second mode capable of exerting adverse impact even in the absence of any active therapy.   

This same dual mode can be seen with other agents: grapefruit juice (GFJ) exhibits strong - and strongly adverse - impact via its antioxidant furanocoumarins components bergamottin, naringin, and dihydroxybergamottin. Given this, it would be prudent to avoid all coadministration with, for example, exemestane (Aromasin), and of course with the other chemotherapies noted above as well as the vast number of other CYP3A4-mediated drugs exhibiting adverse interactive activity, as witness the well-known, extensively documented, fatality of a 29-year healthy man and allergy sufferer who consumed just two glasses of grapefruit juice while taking terfenadine (Seldane) antihistamine medication, which induced fatal cardiac arrhythmias via prolongation in the QT interval, by virtue of CYP3A4-mediated highly toxic elevated levels of terfenadine
198. And the window of potential exposure is wide: at least 24 hours, since 24 hours after ingestion of a glass of grapefruit juice, 30% of its effect is still present and active199,200,201, and  under some circumstances some small but appreciable activity may still be present at 72 hours post-ingestion.

But in a different mode of action, grapefruit (whole fruit) consumption itself has been recently associated with elevated risk of breast cancer in a large prospective cohort study of over 50,000 postmenopausal women from five racial/ethnic groups conducted by Kristine Monroe
202 at the USC Norris Comprehensive Cancer Center, which found that grapefruit intake was significantly associated with an increased risk of breast cancer for subjects in the highest category of intake, which was just one-quarter of one grapefruit or more per day, with the minimal consumption of one quarter of a grapefruit daily increasing the breast cancer risk by a distressing 30 percent, via clinically significant increases in plasma estrogen concentration, at alarmingly higher circulating estrogens levels. And although this single study requires further confirmation in other trials to be absolutely dispositive, given broad supportive preclinical and pharmacokinetic data and compelling molecular motivation, it would be prudent for women both cancer-naive and especially those with breast cancer to exercise extreme caution in any significant consumption of dietary grapefruit203.

Given that dietary factors are estimated to account for 30% to 35% of cancer incidence, as found in the seminal studies of Sir Richard Peto, UK's leading epidemiologist and his colleague, the  late Sir Richard Doll
203, these findings on the potentially adverse interaction of dietary factors with various oncotherapeutics, and well as the direct adverse potential of dietary components on various human cancers, independently of any active therapy or relevant interactions, are of especial weight and pertinence in avoidance of associated disease and mortality.


Garlic

O f note, garlic (and other members of the Allium genus) showed dose-dependent dual activity, elevating CYP3A4 mRNA at a lower dose of 0.1 µg/ml, whereas at higher doses garlic produced a decline, and garlic has been independently found to adversely increase the metabolic elimination of the HIV protease inhibitor, saquinavir (Invirase), a CYP3A4 substrate, in patients consuming both the anti-retroviral and garlic concurrently205, this study being the first (but not the last) to demonstrate that garlic supplements, which are widely used, might have a detrimental effect on concomitant medications, expanding on the earlier findings of Brian Foster and colleagues206 at Health Canada besides supplements, fresh and aged garlic exhibited similar detrimental effect.


Furthermore, the Foster study has further helped to clarify this issue: the study tested 6 different garlic supplements (ranging in dose from 10mg to 20mg, equivalent to 1000mg to 2000mg fresh garlic content) inhibited the cytochrome p450 CYP2C19 enzyme by 21% to 53%, and concludes that "constituents of garlic may not need to be present in high levels to elicit a pharmacological effect in order to produce a systemic or pre-systemic effect on drug disposition. The potential for the garlic products examined in this study to affect drug disposition may increase if used in combination with one or more conventional therapeutic products" and more importantly, that "that the disposition of drugs . . . could be inhibited after the co-administration with garlic or garlic products". Note that the metabolism of the widely deployed endocrine agent / aromatase inhibitor letrozole (Femara) is in part CYP2C19-mediated, and so potentially adversely affected by garlic coadministration.


In contrast with these in vitro findings, David Greenblatt and his colleagues207 at Tufts evaluated 8 water-soluble components of aged garlic extract in order to asses potential to inhibit cytochrome-P450 (CYP) enzyme activity, for the CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, observing that none of the 8 garlic components produced >50% inhibition even at high concentrations, except for S-methyl-L-cysteine and S-allyl-L-cysteine, which produced 20–40% inhibition of CYP3A compared to control. They conclude from this that drug interactions involving inhibition of CYP3A enzymes by aged garlic extract are very unlikely.


However, we note the following:

(1) That although their observation there is no available clinical evidence for CYP3A inhibition in vivo by garlic or garlic components is accurate, it should be remember that there is no such in vivo data because no in vivo trial has been conducted to settle the matter one way or the other, so the absence of data for an in vivo inhibitory effect is not to be construed as the presence of positive data that shows no such effect occurs in fact.

(2) That they consider the two exceptions (the S-methyl-L-cysteine and S-allyl-L-cysteine garlic components) of significant 20–40% inhibition of CYP3A as "modest", but a reduction this large, were it to be evidenced in vivo with oncotherapy, would be considered quite dramatic and of grave concern given the narrow therapeutic index of oncotherapeutic agents, and this suggests at least a potential for adverse interaction with such endocrine agents as anastrozole (Arimidex) whose metabolism is CYP3A-mediated, exemestane (Aromasin) which is CYP3A4-mediated, and the CYP3A4-mediated chemotherapy agents the taxanes docetaxel (Taxotere), paclitaxel (Taxol), nab-paclitaxel (Abraxane), or any of the Vinca alkaloids vinorelbine (Navelbine), vinblastine (Velban), and vincristine (Oncovin), and the platinum agent carboplatin. Without in vivo data to demonstrate no clinically significant impact of this CYP3A/3A4-inhibitory activity, the potential for adverse interaction remains (not that although on at least one of these agents, docetaxel (Taxotere) Michael Cox and coresearchers
208 found that garlic did not significantly affect the disposition of docetaxel, nonetheless as the authors admit, it cannot be excluded that Allium vegetables like garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele, and hence coadministration is still problematic, as can not typically pre-identify these populations).

(3) The Greenblatt findings, with respect to CYP2C19 appear to be in direct contradiction to the Foster findings cited above, although Breast Cancer Prevention Watch notes this may be an artifact of the overly permissive and broad definition of significant interaction in the Greenblatt study, which is > 50% inhibition. In contrast the Foster study found that the 6 garlic supplements (ranging in dose from 10mg to 20mg, equivalent to 1000mg to 2000mg fresh garlic content) inhibited the cytochrome p450 CYP2C19 enzyme by 21% to 53%, amounts they observe correctly could "elicit a pharmacological effect in order to produce a systemic or pre-systemic effect on drug disposition".


We see here a classical difference of disposition: for Greenblatt, potential interaction appear to have to exert very large effects (> 50%) before perceived as clinically significant, while for Foster a potential 20% or higher reduction in the activity of a drug (and possibly lower) is taken as significant in reductive capability; more in contrast. Greenblatt takes an optimistic approach to the issue of potential adverse interaction (based on in vitro findings), not observing a notable hazard unless there are explicit data that show an in vivo adverse interaction, while Foster takes a cautionary perspective until in vivo data were to show that the potentially adverse interaction in vitro is not also found in vivo, and absent such evidence, as here, views coadministration as problematic.


Given the narrow therapeutic index of oncotherapy agents, and their potential impact on mortality, Breast Cancer Prevention Watch would suggest erring on the side of caution: after all, for years we have known about a well-documented potentially adverse compromise of tamoxifen efficacy when coadministered with SSRI antidepressants, but many oncologists (but not David Flockhart, a principal in these findings) argued that proactive data of a clinically adverse interaction, coadministration should continue without change (while as many said "the jury is still out").

Others, including ourselves have reasoned otherwise, noting that the absence of demonstration of harm is not equivalent to the demonstration of no harm, and that given the vital operation of tamoxifen, typically administered over years, it would be imprudent to chance coadministration with an SSRI only to learn that indeed the interaction is significant, and adverse, at the clinical level, as this may entail tamoxifen failure, and even consequent patient mortality or disease recurrence due to deployment of an efficacy-compromised endocrine agent like tamoxifen.

On the basis therefore of the above considerations, we agree with the deductions of Sonnichsen and colleagues209 who conclude that "Certain foodstuffs or food constituents, such as, for example, grapefruit, Seville orange juice, red wine, alcoholic drinks in general, or large quantities of caffeine and garlic should be avoided during drug treatment", in keeping also with the results of Alex Sparreboom's and colleagues210 at the NCI in their review, finding that garlic was one of the natural agents with the "potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome P450 isozymes) and/or the drug transporter P-glycoprotein" and which "participate[s] in potential pharmacokinetic interactions with anticancer drugs" and also with the results of Zhou and who found potentially adverse interaction of the dially sulfone component of garlic as a CYP3A4 inhibitor, although an earlier study by Markowitz and colleagues212 found in contradiction that garlic extracts were unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathway of metabolism. Such not wholly convergent findings suggest the need for caution concerning coadministration until in vivo / clinical data are available to settle the issue. 


As can be seen from the above, although we have to date no decisive in vivo / clinical data to either definitely show harm, or the opposite, to definitively show no harm, there remains the potential for adverse interaction between Allium vegetables and certain oncotherapies. One can balance this against the very real potential for other beneficial activities of garlic and Allium components on health, and on cancer, but we don't know how the balance of benefit / harm will swing, hence our own cautionary stance.


Brassica / Cruciferous Vegetables

-- Safety of Sulforaphane?

One final issue on components of brassica vegetables concerns the component sulforaphane: as Zhou et al.
213 observe, this biologically active phytochemical found abundantly in broccoli, can significantly down-regulate cytochrome P450 3A4 (CYP3A4) expression in human primary hepatocytes, and although this mechanism serves as part of the foundation for its anticancer and chemopreventive activity, there may be some potential for adverse interaction with CYP3A4-mediated agents such as exemestane (Aromasin), and we await clinical studies to determine whether such interaction exerts clinically significant impact on concurrent administration (see also Maheo et al.214 who first reported the CYP3A4 enzyme operation in sulforaphane).

And the review of Paolini & Nestle
215 found that "cruciferous isothiocyanates such as sulforaphane, most often considered as beneficial phase-II detoxifying system inducers, turn out to be genotoxics or strong promoters of urinary bladder and liver carcinogenesis as well as inducing cell cycle arrest and apoptosis".

Sulforaphane is an isothiocyanate (isothiocyanates being the family of compounds found in large amounts in cruciferous vegetables in the form of the thioglucoside precursors (glucosinolates)) that has been isolated from SAGA broccoli as the major phase II enzyme inducer present in organic solvent extracts of this vegetable. The (chemo)protective effect of sulforaphane, an isothiocyanate - - which is liberated from glucoraphanin (GRP), its glucosinolate precursor, by myrosinase hydrolysis, is believed to involve the induction of Phase-II metabolizing enzymes which are active in the detoxification of many carcinogens and ROS (reactive oxygen species), and by this protecting cells against DNA damage and subsequent malignant transformation. However, as discovered by Paolini et al.216: (1) in some cases these enzymes also bioactivate several hazardous chemicals, and (2) that despite sulforaphane's projected benefits, overlooked is its unknown effects on the Phase-I enzyme systems involved in the bioactivation of a variety of carcinogens, where not only has sulforaphane been shown to inhibit the CYP2E1 cytochrome P-450 enzyme involved in the activation of a variety of carcinogen, but also to down-regulate CYP3A4 expression (as shown by the separate Zhou and Maheo studies, cited above), and this raises issues of potential significant and possibly adverse interaction with CYP3A4-mediated oncotherapy agents such as endocrine agent exemestane (Aromasin), taxanes (docetaxel (Taxotere), paclitaxel (Taxol)), and nab-paclitaxel (Abraxane) or any of the Vinca alkaloids (vinorelbine (Navelbine), vinblastine (Velban), vincristine (Oncovin)), and the platinum agent carboplatin (Paraplatin), suggesting caution of coadministration of high-sulforaphane-content dietary or supplemental sources with any of the CYP3A4-dependent classes of oncotherapy just notes, until further in vivo or ideally human clinically studies can demonstrate compellingly the safety ands non-problematic nature of such coadministration.


Independent of this, there is another disturbing aspect of sulforaphane’s induction of Phase-I CYP bioactivating enzymes: sulforaphane is as we noted above liberated from its glucosinolate precursor glucoraphanin (GRP), and there is some evidence that GRP may possess co-carcinogenic properties. Indeed, by inducing Phase-I CYP bioactivating enzymes, GRP may trigger the conversion of benzo[a]pyrene to carcinogenic reactive intermediates like diol-epoxides, and recent studies have shown that a cruciferae-based diet containing a selection of brassicaceous vegetable that includes broccoli, Brussels sprouts or cauliflower, leads to a significant increase in Phase-I enzymes such as CYP1A1/2, which can bioactivate PAHs, dioxins, aromatic amines and nitrosamines (as reported by Paolini et al.216, and priorly confirmed as well in the study by Vistisen et al.217 who found that in nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio adversely by an average of 12% compared to a comparable diet of non-cruciferous green vegetable, see also Lampe et al.218.


The adverse impact of the brassica diet not only hinges on adverse interactions across CYP3A4 as documented extensively in this review, but also on CYP1A2 activity and is increased by cigarette smoke, well-cooked meat, and unfortunately by cruciferous vegetables and this is adverse, since CYP1A2 metabolizes various environmental procarcinogens, such as heterocyclic amines (HCAs), nitrosamines and aflatoxin B1, in keeping with the research of Lampe et al.218, where it was found that that under controlled dietary conditions, at moderate levels of intake (428 g), brassica vegetables increased (while apiaceous vegetables decreased, and allium vegetables did not change) CYP1A2 activity by 18 - 37%, when compared with a basal, vegetable-free diet.


-- Brassica / Cruciferous Vegetables - I3C, DIM

Epidemiological studies provide evidence that the consumption of cruciferous vegetables protects against cancer more effectively than the total intake of fruits and vegetables. The indole-3-carbinol (I3C) component in brassica and cruciferous vegetables may also be protective in cervical and possibly prostate cancers, probably by enhancing 2-hydroxyestrone (an estrogen receptor antagonist - non-stimulative of breast tumors - produced in estrogen breakdown) at the expense of 16-hydroxylation (an estrogen receptor agonist - promoting breast tumors - also produced in estrogen breakdown), thus shifting the ratio to the favorable estrogen breakdown product219. Epidemiological, laboratory, animal and translational studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial and cervical cancers220,221,222. However, there are significant concerns surrounding the issue of potential adverse interactions through the P450 cytochrome family of enzymes, especially on the hepatic microsomal metabolism of tamoxifen (TAM): so Daniel Parkin and Danuta Malejka-Giganti223 at the University of Minnesota in another in vivo study found that although metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM was increased 3-fold by I3C, and since N-desmethyl-TAM is transformed to a genotoxic metabolite, this appears to suggest that dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat.

However, here again, conflicting results exists: so Dustin Leibelt and colleagues224 at Oregon State University failed to detect any direct toxicity by long-term exposure to I3C and DIM, even at doses up to approximately 5–7 times the daily dose recommended by commercial suppliers of I3C supplements, and at exposure 10 times higher than the current human dose for DIM, and the researchers concluded that data from their present study confirms results from short-term studies indicating that both I3C and DIM are relatively nontoxic compounds, and furthermore confirm earlier long-term feeding studies in other models, including the rainbow trout and the same strain of rat used in the present study, that I3C is not a complete carcinogen, a finding also confirmed by Gary Stoner and co-researchers225 who nonetheless warn that I3C may not an appropriate chemoprotective agent for human use in that it appears to both inhibit (breast, colon) and promote (liver) carcinogenesis. And the Leibelt study warns of two distinct concerns: (1) that the prolonged use of I3C for cancer chemoprevention exhibits a potential for promotion of liver neoplasms, although they prudently admit that the long-term post-initiation effects of I3C in hepatocarcinogenesis are not consistent across species (trout, rats, black mice), leaving open what the real risk is, if any, in the human context; and (2) the induction of CYP enzymes by I3C, especially those of the 1A subfamily, could be a cause for concern, as these play a role in activation of polycyclic aromatic hydrocarbons (PAH) and aromatic amines with known toxicities, a concern that appears not to be shared with DIM. The reason for this may be that in the acidic conditions of the stomach after oral exposure, I3C becomes a complex mixture more than 20 different I3C-derived compounds, including DIM, all having various pharmacological/toxicological effects, while DIM is relatively more stable in acid and does not robustly undergo further condensation reactions, suggesting that the more stable DIM component may be the safer compound to deploy in the human context.

However, I3C yielded dose-dependent increases in the hepatic P450 level according to the research of Malejka-Giganti and coresearchers226 at the University of Minnesota who in their animal study of female Sprague-Dawley rats tested 5, 25 and 250 mg/kg body weight of I3C and DIM at 8.4 and 42 mg/kg body weight, finding that oral intake of I3C or DIM at lower dose levels did not alter CYP-mediated metabolism of tamoxifen, and hence, would not alter its therapeutic efficacy. Since for a human female weighing 140 lbs, equivalent to about 64 kilograms (kg), the CYP-mediated TAM metabolism altering dose (250/mg/kg) would map to 16,000 mg, which is easily 40 times greater than the recommended I3C dosing of 400mg/daily, and from these findings it would appear that doses up to 1600mg/daily would be without adverse interactions on tamoxifen metabolism and efficacy, assuming the same 140 lbs female, and that 400mg/daily IC3 ingestion is at a level to assure no oncotherapy interference with tamoxifen -  but given conflicting findings in the  evidence base, this can be no means be considered dispositive.

Thus, we note the conclusions of a comprehensive review by EG Rogan227 with the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center who notes that "although I3C has been shown to protect against tumor induction by some carcinogens, it has also been observed to promote tumor development in animal models" and that in humans, concerns have been raised that I3C might increase the formation of estrogen metabolites that induce or promote cancer". In this connection, the in vivo component of I3C, 3,3'-diindolylmethane (DIM) is unlike, its precursor, I3C itself, not highly enzyme-inducing, where it appears from the evidence base that it is the unwanted enzyme induction by I3C that accounts for any perceived adverse tumor promotion activity by I3C, and lacking these unwanted enzyme-inducing effects, DIM, which appears to share the positive efficacy of I3C in breast and cervical carcinomas, would be suggested as the safer compound in human use (and in keeping with the conclusion of Leibelt, cited above, that "Long-term exposure to DIM produced no observable toxicity, and comparison to I3C indicates that DIM is a markedly less efficacious inducer of CYP in the rat at doses relevant to human supplementation").


-- Further Evidence of CYP-mediated Potential Harm of Brassica / Cruciferous Components

Against this, animal studies have strongly suggested promotion of endometrial adenocarcinoma by I3C which appears to be correlated with the induction of CYP1A and CYP1B enzymes and sequential formation of toxic estradiol catechol metabolites, suggesting AhR-mediated pathways may be critical228, and with respect to DIM, in vitro studies have shown it to exhibit estrogenic activity in certain cancer cells, via ligand-independent activation of ER229,230,231

In addition, it now appears216 that regular administration of the glucosinolate precursor glucoraphanin (GRP) by myrosinase hydrolysis actually increases rather than decreases cancer risk, especially for individuals exposed to mutagens and carcinogens in the environment (e.g., tobacco smoke, and other certain industrial exposures), via phase-II metabolizing enzymes which, although generally have been taken as beneficial, can bioactivate several hazardous chemicals. And we are nonetheless left with unknown effects of brassica / cruciferous even on phase-I enzyme systems involved in the bioactivation of a variety of carcinogens, which induce phase-I carcinogen-activating enzymes including activators of carcinogenic PAHs (polycyclic aromatic hydrocarbons), and concurrently with this phase-I induction GRP over-generates reactive oxygen species (ROS) while also facilitating the metabolic activation of the PAH benzo[a]pyrene to reactive carcinogenic forms, along with observed DNA-damaging genotoxicity. And these adverse effects were seen at dietary-realistic levels, as Moreno Paolini at the University of Bologna and coresearchers (see previous) have demonstrated: despite glucosinolate content in brassica / cruciferous vegetables varying with species, cultivation, and the parts of the plant used, the mean content was 100 mmol/100 g fresh weight (a typical portion of vegetables), corresponding to 26 mg GRP (55% of the total), which was sufficient to induce a powerful and highly significant increase (from 4.4 to 13-fold) of several phase-I carcinogen-metabolizing enzymes following a single or repeated treatments of GRP, with a significant increase in CYP1A1/2 enzymes which activate polychlorinated biphenyls, aromatic amines and PAHs, CYP3A1/2 enzymes activating nitropyrenes, aflatoxins and PAHs, CYP2B1/2 enzymes activating olefins and halogenated hydrocarbons) and CYP2C11 enzymes activating nitrosamines, aflatoxins and ochratoxins, all of which led the researchers to conclude that "The observed CYP induction following GRP administration suggests that GRP may possess co-carcinogenic properties"216 (see also Lampe et al.218). This brassica / cruciferous components like GRP may instead of behaving chemopreventively, in fact exert adverse toxicological effects via the induction of carcinogen-bioactivating enzymes, and via generating oxidative stress and genotoxic DNA damage, of especial concern for individuals exposed to mutagens and carcinogens known to be metabolized by phase-I bioactivating enzymes, include of course cancer patients who have have impaired DNA repair mechanisms (also in agreement with Paolini & Nestle215.

Another potential for harm comes from a wholly different mechanism - activation of estrogenicity: researcher Jacques Riby and colleagues at the Division of Nutritional Sciences and Toxicology of University of California, Berkeley found that DIM (3,3′-Diindolylmethane) - a major in vivo product of acid-catalyzed oligomerization of I3C (indole-3-carbinol) present in brassica vegetables like broccoli and others in the  genus - is a promoter-specific activator of estrogen receptor (ER) function in the absence of (17β-)estradiol, inducing proliferation of these cells in the absence of steroid, suggesting promoter-specific, ligand-independent activation of ER signaling by DIM, functioning as therefore a selective activator of ER function232


-- Warning: Insufficiency of Myrosinase Inactivation of Dietary Brassica / Cruciferous Components

It is often cited in defense of the safety of brassica / cruciferous consumption concurrently with various oncotherapies whose metabolism is CYP-mediated across the same p450 CYP enzymes that are influenced by brassica / cruciferous vegetables, that cooking can inactivate myrosinase, the enzyme which hydrolyzes glucosinolates in cruciferous and brassica vegetables into biologically active isothiocyanates (ITC). However, the fallacy here is the failure to realize, well-documented, that even if myrosinase has been inactivated, intestinal microbial metabolism of glucosinolates also contributes to ITC exposure233, as colon microflora appear to be able to catalyze glucosinolate hydrolysis when vegetables are cooked, so that isothiocyanates still arise despite cooking, and although this is apparently at a lower level (10% to 20%), there is absolutely no reassuring data to show that such activation by bacterial myrosinase isn't sufficient to support adverse interaction with active oncotherapy. It isn't just the range of methods used to prepare these foods and the associated degree of myrosinase inactivation that determines potential adverse interaction, but also the activity level of the consumers’ dentition / chewing, as well as the consumer's colonic microbes, that all contribute to an individual's risk exposure, and indeed this is also dependent on genetic polymorphisms in biotransformation enzymes that metabolize ITC, and possibly as well receptors and transcription factors that interact with these compounds, all factors independent of cooking inactivation and contributing wide individual variation which may sustain adverse risk at clinically significant levels in any one individual (on bacterial glucosinolate metabolism occurring in the digestive tract and the  modulate of the process of glucosinolate metabolism in relation to the composition and activity of the colon microflora, see Krul et al.234). And direct evidence of colonic hydrolysis of glucosinolates in human subjects themselves has been provided in a study by Serkadis Getahun and Fung-Lung Chung235 with the American Health Foundation which documented a linear increase in the formation of isothiocyanates for 2 hours after incubating with bowel microflora cooked watercress containing glucosinolates but no plant myrosinase.


And as Lilli Link at Columbia and John Potter at the Fred Hutchinson Cancer Research Center have noted, the average excretion of isothiocyanates in the 24-hour urine collection was still a non-trivial 20.6 µmol even in human subjects who ate broccoli steamed for 15 minutes237, confirmed also in the earlier research of Clifford Conaway's team at the American Health Foundation236), and this independent of possibly further enhancement of level under variable circumstances of the additional affecting factors such as gut microflora, pH and the presence of various cofactors. Furthermore, glucosinolate hydrolysis in the gut can produce a range of breakdown products in addition to the isothiocyanates, and the yields of such different groups of metabolites, including isothiocyanates, nitriles and epithioalkane nitriles, and the factors that may affect these yields after glucosinolate ingestion, are not well understood, but the delayed release of isothiocyanates in significant quantities after cooking - which supposedly should have inactivated such production - has been decisively demonstrated recently by Gabrielle Rouzaud's team238 at Aberdeen, via the action of the colon microflora when dietary glucosinolates reached the colon, and such colonic hydrolysis - as opposed to and in addition to myrosinase-mediated hydrolysis - of glucosinolates may yield other active products such as nitriles in addition to isothiocyanates. Finally, it has been shown by Fekadu Kassie's team in Vienna collaborating with the UK Institute of Food Research that juices of Brussels sprouts, white and green cabbage, cauliflower, kohlrabi, broccoli, turnip, and black radish all induce pro-mutagenic genotoxic activity239.

Another fallacy should also be noted here: not all brassica / cruciferous vegetables are created equal: although heating to 70 °C and above decreased the formation of both sulforaphane and sulforaphane nitrile products in broccoli florets, this was not true of broccoli sprouts, whose sulforaphane content was unaffected by such heating
240, and compared to boiling, cooking by steaming, microwaving and stir-fry did not produce significant loss of glucosinolates the content of the 7 major glucosinolates in broccoli, Brussels sprouts, cauliflower and green cabbage241,242,243.   


The prudent and cautionary advice of Gary Stoner at Ohio State University is therefore worth remembering: "With the exception of the studies cited in this report (6,22,23), no other attempts have been made to weigh chemoprotective benefits against promotional risk for I-3-C. In spite of the hope that I-3-C might be a non-genotoxic alternative for tamoxifen or synergin for adjuvant therapy, the risk of promoting colon and liver cancer, especially if I-3-C is used as a `health food' by the presumably disease-free general public is unwise and potentially dangerous"225.  Similarly, Roderick Dashwood at the University of Hawaii who notes that some studies "provide clear evidence for promotion or enhancement of carcinogenesis, depending upon the initiator, exposure protocol and species. In the absence of detailed information on the inhibitory and in particular, promotional mechanisms, it would seem advisable to proceed with caution before including I3C in extensive human clinical trials"244.


Summary of Adverse Food-Oncotherapy Interactions, Known To Date

The major food items with some evidence of potentially adverse interaction during concomitant oncotherapy across the cytochrome p450 hepatic enzyme system are:

  • brassica / cruciferous vegetables
    [arugula, bok choi, broccoli, brussel sprouts, cabbage, cauliflower, collards, daikon, horseradish, kale, kohlrabi, mizuna, mustard greens, napa (or Chinese) cabbage, radish, rutabaga, tatsoi, turnips, wasabi, and watercress]

  • Note: garlic powder remains unproblematic if and only if used not at food-item-levels but at light seasoning-levels (no more than a sprinkling or "small pinch")

  • the juice and fruit of grapefruit and seville oranges;

  • the juices of wild grape, pomegranate, and black raspberry (and probably others not yet tested);

  • extracts and teas of licorice, goldenseal and chamomile;

  • evening primrose oil (EPO) and borage oil;

  • the spices sage, thyme, and cloves
    (which like garlic powder, remain unproblematic if and only if used at light seasoning-levels)


with these findings subject to change and refinement under additional data.


-- Apiaceous Vegetables

Against this adverse impact of brassica vegetables, Breast Cancer Prevention Watch finds intriguing the fact that apiaceous vegetables (carrots, parsnips, celery, dill and parsley) decreased mean CYP1A2 activity by ~13–25%, which suggest to us - but note without any clinical data to support the hypothesis - that the differential CYP1A2 response to the brassica and apiaceous vegetable diets
may be leveraged to in largely past cancel out or nullify the adverse CYP1A2 impact of the brassica components by co-consumption with apiaceous vegetables.


-- Lapatinib Dosing and Meal-based High-Fat Consumption

Given all the negative press on the potential adverse interactions CYP3A4-metabolized drugs and CYP3A4 inhibitors or inducers, we have recently encountered a new twist on the theme, the suggestion that such interaction could be leveraged positively, even to economic advantage. So Allison Grandley, writing for Medscape Medical News, quote University of Chicago oncologists Mark Ratain and Ezra Cohen
245 to the effect that "Simply by changing the timing — taking this medication with a meal instead of on an empty stomach — we could potentially use 40% or even less of the drug" and that "Since lapatinib costs about $2900 a month, this could save each patient $1740 or more a month"246. Colleague and co-author Dr. Cohen continues with faint caution, suggesting that "Dozens, if not hundreds, of drugs should be studied in this way, the authors suggest. "If we understood the relationship between, say, grapefruit juice and common drugs, such as the statins, which are taken daily by millions of people to prevent heart disease, we could save a fortune in drug costs"245

We would strongly advise against any such suggestion, and in fact - apparently unknown to writer Allison Grandley - the authors of the study, Marc Retain and Ezra Cohen of the University of Chicago, do NOT in fact themselves advise taking lapatinib at reduced dose with a meal, despite their soaring rhetoric to the media; they state clearly in their article that they "
do not recommend off-label administration of lapatinib outside of a clinical trial"246, and to do otherwise would of course have grave medico-legal implications for the authors, as despite the appearance to the contrary there is not one iota of clinical data to suggest the safety and efficacy of any mode of administration of lapatinib other than the sanctioned fasting mode, nor for the safety and efficacy of lapatinib at any dose reduction from the sanctioned schedule, whether with or without food. Meal-based dose reduction may potentially compromise the treatment benefit of an effective therapy for advanced or metastatic breast cancer: fasting conditions are, by definition, reproducible, whereas taking a meal (along with a long-term drug administration by oral route) is not replicable and an obvious source of heterogeneity in terms of inter-patient and/or intra-patient pharmacokinetic variability. The risk of taking lapatinib with food (no matter if standardized or not) is to generate grossly unpredictable plasma concentrations and to consequently worsen efficacy and/or adverse effects. The pharmacokinetic data on lapatinib clearly indicate that decreasing the dose and using the contents of a meal to adjust bioavailability in order to achieve therapeutic plasma concentrations is not only unreliable but potentially highly dangerous. Dietary manipulations with inconsistent effect on drug exposure are to be avoided in clinical use, as the clinical benefit of such maneuvers unknown and potentially of significant harm to patients via compromising a drug's efficacy or toxicity.

Furthermore, it should be noted that the Dartmouth study by Nandi Reddy
247 that Marc Retain and Ezra Cohen of the University of Chicago cite as support is a phase I open label pharmacokinetic study that suggests that full dose, not reduced dose, lapatinib exposure is significantly increased when taken with a high-fat meal as compared with a fasted state; the authors of this article did not study the exposure from a lower dose of lapatinib (250 or 500 mg) taken with a meal compared to the 1,250-mg dose taken 1 hour before or after meals, and so such exposure is unknown, and hence this study is wholly insufficient to found any conclusion about reduced-dose lapatinib, such a conclusion requiring further clinical studies including a relative bioavailability study evaluating lower lapatinib dose taken with a meal versus a 1,250-mg dose taken without a meal. Overlooked by Retain and Cohen are both inter- and intra-patient variability in bioavailability, along with dietary effects on concomitant medications, and differing patterns of oral intake and food constituents. Individual food intake varies from time to time, and the meal's composition (caloric intake and fat, protein, and carbohydrate content) can have erratic and unpredictable effects on gastric emptying and intestinal motility in any given individual, resulting in no reliably assured drug level. Indeed, FDA submitted preapproval clinical studies examined the average increase in lapatinib's bioavailability with a low-fat and a high-fat meal, and found that individual patients taking the recommended dose with food will have highly variable (52% coefficient of variability) and unpredictable changes in absorption248. Data presented by Nandi Reddy of Dartmouth Hitchcock Medical Center during the ASCPT meeting (see above) showed that this food effect showed broad variability between individual patients, with 48% inter-patient variability in apparent oral clearance, yielding 68% variability in AUC systemic exposure (area under the curve). However, this still underrepresents the magnitude of variability experienced across individual study, sometimes dramatic in range, from a slight decrease to as high as a 24-fold increase, and as Kevin Koch and GlaxoSmithKline (GSK) coresearchers249 have observed, participants in the controlled studies ate precisely identical meals at the same time and consistently each day as required by the protocol, an artificial scenario rarely if ever seen in the real world. Unfolding in such eating pattern variations may countervail proposed cost savings by increased toxicity or unfortunate disease progression if appetite were sufficiently depressed or inter-patient variability dealt some unlucky patient a suboptimal plasma level of the agent.

And as noted by Atiqur Rahman with CDER at the FDA (see Rahman et al., above), the AUC ratios (fed/fasted ratio) could range from less than one for some individuals to as high as 24-fold increased exposure if accompanying a high-fat meal, translating to the scenarios of some patients being under-dosed while others being massively and dangerously overdosed from the mean-adjusted dose of lapatinib. This is especially serious given the QT prolongation potential of lapatinib, as found in a dose escalation study in patients with advanced cancer which observed a relationship between lapatinib concentration and the QT interval, so that high concentration induced artificially by food consumption and food content manipulation could led to highly adverse cardiac events such as cardiac rhythm disturbances including fatal cardiac dysrhythmias like torsades de pointes
250. The US FDA Clinical Pharmacology and Biopharmaceutics Review250 documents lapatinib-induced QT prolongation, noting that administration of lapatinib with food "would be expected to further prolong the QTc interval" a risk factor for torsades de pointes and/or sudden death251.

The authors Ratain and Cohen even less prudently offer a suggestion that even greater cost savings might be achieved by drinking grapefruit juice with food to further boost bioavailability, this despite the large body of literature demonstrating the highly variable effect of grapefruit juice with bioavailability being modulated in either direction due to multiple effects on metabolic enzymes including the hepatic p450 cytochrome system, and intestinal and hepatic drug transport proteins (see Koch et al., above)), with well-documented adverse consequences, possibly also increasing the risk of serious toxicity from other drugs prescribed concomitantly. We simply do not want to add to the erratic and generally adverse interactions from furanocoumarins like the bergamottin component of grapefruit juice. To offer a final cautionary scenario: a patient, following the Retain-Cohen suggestion, consumes reduced dose (250 - 500mg) of lapatinib with a high-fat meal, but for this patient - and possibly for this meal among many others - the predominant fat contribution comes from soy-based fat via soybean, which would in turn deliver high daidzein and genistein isoflavone soy components. But these soy components are CYP3A4-mediated in metabolism -and, unfortunately, lapatinib metabolism, and hence both its safety and efficacy, is also severely CYP3A4-mediated, therefore leading to potential highly adverse drug-food interaction over the p450 hepatic cytochrome enzyme system. In any rational and moral approach to drug administration, we cannot accept that some patients get unlucky by virtue of meal composition. In a fasting state, all patients are created equal.


A Plea for Consistency

The TAM-SSRI Lesson

But recent developments support our cautionary stance: the results by SK Knox and coresearchers252 reported at the June 2006 ASCO meeting found that in patients that coadminister tamoxifen and an CYP2D6-inhibitory agent such as an SSRI or other inhibitory agent (fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), cimetidine(Tagamet), amiodarone (Cardarone), doxepin (Adapin/Sinnequan), ticlopidine (Ticlid) and haloperidol (Haldol) were tested), had significantly worse time to recurrence (TTR) and disease free survival (DFS), in the real human clinical setting, and a large body of robust RCTs, systematic reviews, and meta-analyses such as the recent (May 2013) meta-analysis of Zhiyu Zeng and colleagues253 reviewing 20 eligible studies on tamoxifen and CYP2D6 polymorphisms (n=11,701) found that CYP2D6 polymorphisms may influence tamoxifen treatment outcomes as to disease-free survival (DFS) in breast cancer patients.


But that puts many oncologists in the embarrassing position of having countenanced significant adverse impact on patient outcome on the basis of an optimistic stance that, after all, only the potential for harm had priorly been demonstrated, not actual harm; with the Knox findings we now know retrospectively that the potential was real and did translate into adverse impact of patient outcome in terms of both disease recurrence and survival, and so this seriously degrades the value of any optimistic stance on these matters.


Indeed, the stance most oncologists took on the above issue - of the potential compromise in the antitumor efficacy of tamoxifen by concomitant administration of SSRI antidepressants - was not only inconsistent, but would appear hypocritical, as the attitude was "the jury is still out" so co-administration should continue.


Yet as to comparable potential adverse interactions between oncotherapeutic agents and various agents, the vast amount of which was based solely on in vitro, not in vivo or human clinical data, oncologists typically argue strongly that against co-administration, regardless of here too "the jury being out" (and after all, we have a perfectly good solution to the TAM-SSRI interaction problem: use a NSRI such as the highly effective antidepressant (and hot flash relief) venlafaxine (Effexor).


Antioxidant/Oncotherapeutics Co-Administration
Lack of Robust Evidence of Harm



Similarly, oncologists typically argue strongly against co-administration of antioxidants and oncotherapeutic agents, yet on the balance of the evidence, the preponderance of data suggests a synergistic or at least harmless effect with most high-dose dietary antioxidants and chemotherapy, and claims to the contrary are inconsistent and not supported by the evidence data, in that if antioxidants were in reality a significant threat to the efficacy of standard CT and RT, antioxidant-rich foods like fruits and vegetables would also be prohibited during therapy, but no rational oncologist would make such a recommendation (in part because studies have supported the positive benefit of such consumption to overall health and QOL (quality of life)).


In addition, there is again an inconsistency and evidence-based research, and our own review, has already challenged this inconsistency from another more critical vantage point: synthetic antioxidants are already in wide-scale use by both medical and radiation oncologists to control the adverse effects of cytotoxic CT treatments. There are several radioprotectant and chemoprotectant agents that are widely used in conventional oncology whose principal mode of activity is antioxidative such as the highly effective and successful amifostine (Ethyol), used as a radio-protective and cytoprotective, mesna (Mesnex) a bladder-cytoprotective, dexrazoxane (Zinecard) a cardioprotective against oncotherapy cardiotoxicity, and pentoxifylline (Trental), a radioprotective used to treat RIF, radiation-induced fibrosis, all antioxidants. The research on metastatic breast cancer of Keith Block254 at the Center for Integrative Cancer Care and University of Illinois, among many others, suggest that patients who received chemotherapy with antioxidant support at their clinic had better outcomes rather than the non-observed interference by antioxidants of conventional CT therapies. This raises a consistency problem for any oncologist who argues that antioxidants should not be co-administered with oncotherapies, but it would appear that comparable conventional antioxidants (all FDA approved for use for their benefits via their antioxidant activity) are coadministered and apparently without adverse interaction or interference.  For example, amifostine, a pharmacological antioxidant used as a cytoprotectant (protecting normal tissues relative to tumor tissue - that is, both as a  chemoprotectant and as a radioprotectant - was reviewed and found to exert protection against mucositis, esophagitis, neuropathy (but not against cisplatin-induced ototoxicity), with no evidence of tumor protection observed255.


Keith Block at the Institute for Integrative Cancer Research and Education and coresearchers recently conducted a systematic review256 of 19 RCTs on the efficacy of coadministration of antioxidant supplementation with chemotherapy evaluating Vitamin A, Vitamin C, Vitamin E, melatonin, NAC, ellagic acid, glutathione, and an antioxidant mixture in subjects with predominantly advanced or relapsed disease. They found that none of the trials found any evidence of significant decreases in efficacy from antioxidant supplementation concurrent with chemotherapy, with many of the studies finding that antioxidant supplementation yielded either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls, although they note that lack of adequate statistical power was a consistent limitation, so that large, well-designed studies of antioxidant supplementation concurrent with chemotherapy are further warranted. See also the review of Moss who concluded that "A blanket rejection of the concurrent use of antioxidants with chemotherapy is not justified by the preponderance of evidence at this time"257, and similarly for radiotherapy, concluding that "the preponderance of evidence supports a provisional conclusion that dietary antioxidants do not conflict with the use of radiotherapy in the treatment of a wide variety of cancers and may significantly mitigate the adverse effects of that treatment"258. This is cross-confirmed in other reviews259,260 which concluded  from their review (since the 1970's) of 280 peer-reviewed in vitro and in vivo studies, including 50 human studies involving 8,521 patients, 5,081 of whom were given nutrients, that this comprehensive evidence base consistently shows that antioxidants "do not interfere with therapeutic modalities for cancer", and that furthermore, it appears that "non-prescription antioxidants and other nutrients enhance the killing of therapeutic modalities for cancer, decrease their side effects, and protect normal tissue", with 15 human studies of 3,738 patients actually suggesting increased survival.

The subtle and complex issue involved in this arena are demonstrated by the exchange between Brian Lawenda at the Naval Medical Center San Diego and Jeffrey Blumberg at Tufts on the one hand, as per their JNCI article
261, and their several respondents. Finally, with respect to the Lawenda JNCI article, it should be noted that (1) it ignores the two reanalyses and reinterpretations of the seemingly negative Bairati study which in fact shows no harm to coadministration of antioxidants and radiation therapy except for patients who also smoke during therapy (see immediately below for full discussion), and (2) the Lawenda article actually found that antioxidants may enhance the effects of chemotherapy as well as diminish its toxicity ("no decrements in tumor response rates or survival rates were observed" they conclude) yet the study abstract counterfactually states that supplemental antioxidants should be discouraged during both chemotherapy and radiation, in contradiction of their own conclusions within the article itself, especially regrettably since virtually all popular media solely read the abstract not the full paper, as did many health professionals themselves, hence leading to a trumpeting of an injunction against coadministration of antioxidants and oncotherapy (chemo and radiation therapy) not supported by the evidence (like the somewhat hysterical and wholly erroneous headline from Randy Dotinga in HeathDay: "Cancer Patients Should Steer Clear of Antioxidants Research - review suggests they may help cancer cells resist chemo, radiation").  We have often remarked on the dangers of lay misinterpretation of complex medical research findings, and of lay and professional reading of only article abstracts not the full text, and moreover doing so uncritically, without the skills for methodological appraisal, and this adds another case in point.     


Much of the motivation for a prohibition against coadministration of antioxidants with radiation therapy comes the widely cited study of such coadministration in head and neck cancer patients conducted by Isabella Bairati and colleagues262 which gave (synthetic)  alpha-tocopherol and beta-carotene supplements to patients at high risk of second primary cancers.  Higher rates of second primary cancers, along with more recurrences, were found in the supplementation group, with higher all-cause mortality and a trend towards higher cancer-specific mortality during supplementation. These negative findings were disseminated and cited widely in the professional literature and in the popular media, and to this day account for much of the common and pervasive belief in the oncology and radiology communities that antioxidant coadministration with chemotherapy or radiotherapy must be avoided as such practice may lead, as per the study results, to actual harm and effect outcome adversely.

Unfortunately, what the professional communities and the lay public failed to realize - even to this day - was that the findings are in fact in error:  analysis of Bairati’s study population by Francois Meyer at Laval University and coresearchers
263 established that the observed excess recurrences were restricted to only those patients on supplementation who continued to smoke throughout radiation therapy, suggesting that the efficacy of radiation therapy was reduced only by the combined exposures, since for nonsmokers receiving supplements, the hazard ratios hovered near one so that there no was excess risk of mortality compared to the placebo group and hence no adverse effect of supplementation.  Thus patients who either do not smoke or quit smoking during therapy may accrue the benefits of antioxidant supplementation for the reduction of side effects, and without affecting therapeutic efficacy of the radiation therapy.

The same team of researchers undertook another reanalysis
264 of the Bairati study which found, against the putative negative interpretation of  the study, that those patients with the highest dietary intake of beta-carotene actually had significantly fewer radiation side effects, and that furthermore those patients with the highest plasma levels of beta-carotene also had a 33% reduction in local recurrences, clearly not only not adversely affecting therapeutic efficacy of the radiation therapy, but also providing improved outcome via recurrence reduction.  When the antioxidant was allowed to do its work without the ill effects of tobacco, its ability to reduce side effects without affecting therapeutic efficacy was shown. Thus, a leading study put forth to suggest that antioxidants provide a protective shield to tumors during radiation therapy is found (in the absence of concurrent smoking) to actually establish no such thing, but rather to suggest that coadministered antioxidants and radiotherapy not only protect patients from therapy-induced side effects, but also benefit outcome by reduction of recurrence (also concluded by numerous other studies, including the recent review of Paul Okunieff and colleagues265 at the University of Rochester Medical Center).
 

A more recent (2008) systematic review266 examined 33 RCTs on the effect of concurrent antioxidant supplementation on chemotherapeutic toxicity evaluated Vitamin A, Vitamin E, melatonin, NAC, ellagic acid, glutathione, L-carnitine, selenium, CoQ10, and an antioxidant mixture in subjects with predominantly advanced or relapsed disease. It found that the majority (24) of the studies demonstrated evidence of decreased toxicities from antioxidant-chemotherapy coadministration, nine studies reported no difference in toxicities, with only 1 study on Vitamin A reporting a significant increase in toxicity in the antioxidant group. In addition several (5) studies found that the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. And although statistical power and poor study quality were concerns with some studies, the authors concluded that there is evidence antioxidant-chemotherapy coadministration holds potential for reducing dose-limiting toxicities, and without affecting therapeutic efficacy of the therapy.

In sum, just as there can be no blanket disjunction against all coadministration during chemotherapy or radiation therapy, neither however can there be a blanket inclusion, and each CAM agent and intervention must be critically assessed, as witnessed are detailed coverage above of several specific natural agents that require caution against coadministration by virtue of potentially adverse interactions with oncotherapies.  


Myth and Science: The Strange Case of Warfarin

Joanna Marino and colleagues270 reviewed the literature on warfarin and supplement interactions, finding wide variability in the quality or reports and noting that the high preponderance of the data on this issue was derived from case reports or from an extrapolation from supplement mechanisms of action that would suggest such potential interaction, but that the strength of evidence was lacking for the majority of the herbal products reviewed, making firm conclusions impossible.

But we have data that suggests that potential adverse interactions between warfarin and CAM agents have been overemphasized and may in fact be of limited clinical relevance. First in a retrospective cohort study of CAM agents and warfarin in matched control (246 warfarin and 246 control group patients), Munad Khan and colleagues269 at the University of Melbourne found that in the warfarin group, CAM users and non-users reported a similar number of events below and above their therapeutic INR range and when the INR exceeded a reading of 5. CAM users exhibited a similar number of clotting events (9% vs 10%) compared to CAM non-users in the warfarin group, and although they tended to have more abnormal bleeding events (42% vs 30% than CAM non-users, these events were uncommon and the finding may have occurred by chance as the authors candidly acknowledge. Second Vivian Leung and colleagues271 at the University of British Columbia conducted a cohort study of the effects of CAM usage concurrent with warfarin, finding that there was no significant difference in CAM use or consumption of vitamin K-rich foods between patients with and without INRs greater than 4 or for patients with and without INRs less than 2, and that exposure to CAM was not associated with an increase in the risk of self-reported bleeding or out-of-range INR. Third, Shahzad Hasan and colleagues272 in Malaysia conducted a cross-sectional study CAM and concomitant warfarin usage, finding that of those being at risk of potential interactions between warfarin–CAM and warfarin–conventional medicines (such as those co-consuming fish oil, vitamin E, glucosamine, garlic, chondroitin and evening primrose oil), there was no significant difference in the mean INR between CAM and non-CAM users, and all the patients in the study had INR values within the target range. Although not dispositive, collectively the findings from these studies cited are reassuring as to CAM-warfarin co-administration.

We must also remember that (1) most studies and case reports failed to tightly control for the fact the most patients on warfarin experience bleeding events and out-of-bounds INR values, and many also experience clotting events, independent of CAM usage; (2) many patients on warfarin may also be on a polpharmacy of traditional medicines not all of which have been controlled for or even recognized, and many of which have pharmacokinetics of not completely known consequence for such adverse events or potential interactions with warfarin; (3) being on warfarin, such patients are typically subject to – or should be under cautious management – regular PT/INR testing so that out-of-bounds INR readings can be modulated by adjustment of warfarin dosing. Caution need still be exercised but given these considerations and the findings we cited above in this context, it has not yet been decisively established that CAM supplementation represents an excessive and clinically relevant potential for adverse pharmacokinetics with warfarin as to warrant a contraindication, although it warrants diligent monitoring of INR readings which, it should be noted, is however true also for coadministered traditional medicines and even foods.


Selective Warnings:
Contra CAM But Traditional Medicines Ignored

We draw attention to the example of cimetidine (Tagamet) for stomach GI acid complaints: cimetidine is a known and powerful CYP3A4 inhibitor, and dozens and dozens of chemotherapy drugs are metabolized by the same enzyme, making for clinical relevant adverse interactions, yet numerous studies we have reviewed found that oncologists showed no professional caution, or even interest in this, among hundreds of other common adverse interactions among their patients. So researchers267 at the H. Lee Moffitt Cancer Center and the New Hope Cancer Center found that 19% - one in five - of cancer patients were taking cimetidine yet when oncologists involved were informed about the potentially harmful clinically relevant drug combinations - which bore FDA warnings to that effect - not one made any changes in their patients prescriptions. Similarly, Rachel Riechelmann and colleagues268 in Sao Paulo concluded in comparable circumstances that "Curiously, no oncologist made any change in patients’ prescriptions despite being alerted about such interactions by the authors". This suggests that the objection to CAM interventions may be more doctrinal than founded any rational scientific basis, and its selective application against CAM modalities without any comparable inquiry into or prohibition against dozens of traditional medicines far more likely to raise adverse interactions with cancer therapies reflects unfavorably on the sincerity of oncologists' prohibitions against CAM agents; if one is sincerely concerned to minimize the potential for adverse interactions than that should apply to traditional and non-traditional interventions alike, and indifferently, yet regrettably we see no such equity in display. This ultimately leaves the decision in the hands of patients, not a burden they should have to bare alone. Thus, guidance may be stratified and distinguished by the context:
(1) in the advanced refractory and metastatic disease context, many potentially beneficial antitumor agents, both conventional and CAM, may be countenanced given the well known progress of the disease and the typically stark prognosis;
(2) in non-metastatic / non-refractory contexts, the imperative for such use is muted and caution can be weighed and balanced; and
(3) in a disease-naive context - as chemopreventive aid - individual decision can be less constrained as at least the potential for adverse interaction is not present.



Methodology of this Review

A search of the PUBMED, Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, (WoS) Web of Science, BIOSIS, LILACS and Scirus databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.


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