Author:
Dan Labriola, ND and Robert Livingston, MD
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Date Posted: Wed, November 21 2001, 7:31:32 PST
In reply to:
Leonard B. Seeff, et al (NIH) PART 1
's message, "Complementary and alternative medicine in chronic liver disease" on Mon, September 03 2001, 22:45:56 PDT
Vol 13, No 7 (July 1999)
Possible Interactions Between Dietary Antioxidants and Chemotherapy
Dan Labriola, ND
Director , Northwest Natural Health Specialty Care Clinic, Seattle, Washington
Robert Livingston, MD
Division of Oncology, University of Washington Medical Center, Seattle, Washington
Abstract
Introduction
Cytotoxic Actions of Chemotherapeutic Agents
Actions of Antioxidant Compounds
Predictable Mechanisms of Interaction
Implications for Future Research
Implications for Clinical Practice
Conclusions
References
Reviewers' Comments
Kara M. Kelly, MD, College of Physicians & Surgeons of Columbia University, New York, New York
Mark J. Ratain, MD, The University of Chicago, Chicago, Illinois
Readers' Comments and Authors' Responses
Paul Reilly, ND Lac, Mark Gignac, ND, Ben Chue, MD, Manouchehr Sardo, Cancer Teatment Centers of America, Seattle, Washington
Charles M. Bagley, Jr, MD, Northwest Cancer Center, Seattle, Washington
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Many patients treat themselves with oral antioxidants and other alternative therapies during chemotherapy, frequently without advising their conventional health care provider. No definitive studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants in humans. However, there is sufficient understanding of the mechanisms of action of both chemotherapeutic agents and antioxidants to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation. This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action that clinicians may take when patients indicate that they are taking or plan to use alternative therapies. [ONCOLOGY 13(7):1003-1008, 1999]
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Introduction
The popularity of nonconventional therapies, for a myriad of diseases, has increased dramatically. Most patients use some form of alternative therapy, often concurrently with conventional treatment and frequently without advising their conventional health care provider. Relying on media reports, Internet advertising, and industry marketing, many patients believe that nonconventional therapies offer cures for literally every disease, including cancer; that they do not interfere with other treatments; and that they are uniformly free of toxicity at any dosage level.[1]
Dietary antioxidants have received increasing attention from the scientific, clinical, and nutritional foods community.[2-6] Some of that attention has focused on the concurrent use of dietary antioxidants, such as alphatocopherol and coenzyme Q10 with chemotherapeutic agents, such as doxorubicin.[7-10] Claims that such combinations represent novel cancer therapies, without mention of potential interactions, prompt concern for their effect on long-term outcomes. Since many patients treat themselves with oral antioxidants during chemotherapy, clinicians need to formulate a credible position on this subject if they are to provide their patients with timely advice about the potential risks.
To date, no definitive human studies have demonstrated the long-term effects of combining chemotherapeutic agents and oral antioxidants. Fortunately, the mechanisms of action of both are understood well enough to predict the obvious interactions and to suggest where caution should be exercised with respect to both clinical decisions and study interpretation.[11]
This article will describe these potential interactions and areas of concern, based on the available data. It will also suggest several potential courses of action clinicians may take when patients demonstrate an interest in alternative therapies.
Cytotoxic Actions of Chemotherapeutic Agents
Chemotherapeutic agents have many well-defined and suggested mechanisms of actions.[12,13] Some chemotherapeutic agents, including traditional alkylating agents and anthracycline antitumor antibiotics, create reactive oxygen species. Reactive oxygen species are uniformly subject to transformation to more stable compounds by antioxidants through the simple process of electron transfer.[11,14]
Classical alkylators substitute an alkyl group for a proton in organic tissue, as shown below:
RH + XCH2-CH2 ® RCH2-Ch2 + H+ + X
This action is common at the 7 nitrogen atom of guanine, but other sites, such as the 1 and 3 nitrogen atoms of adenine, the 3 nitrogen atom of cytosine, and the 6 oxygen atom of guanine, may also be alkylated. This alkylation of biologically vital macromolecules, such as DNA, and the complex degradation reactions that follow result in the known cytotoxic action of these drugs.
These cytotoxic actions are, however, vulnerable to interference. It is known, for example, that greater concentrations of free thiol groups are present in animal tumors with greater resistance to alkylating agents. In addition, cysteine, a member of the thiol group, can considerably reduce the antitumor effects of alkylating agents.[15]
Thiol groups take the form, R1-S-H. Cysteine tends to lose protons by ionization more readily than do other amino acids with nonpolar R groups, and is often found in its oxidized form in proteins, namely, cystine. It is likely that cysteine reduces the cytotoxic effects of alkylating agents by interfering with the alkylation process and subsequent reactions.
Other chemotherapeutic agents form different primary reactive oxygen species. For example, doxorubicin, in hepatic microsomes in vivo, increases the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) and the transfer of electrons to molecular oxygen, resulting in the formation of anion radicals O2.[15-17]
Actions of Antioxidant Compounds
Antioxidant compounds have a wide variety of actions. They can interfere selectively with free radical initiation, propagation, and termination. They are a normal part of the human diet and have been studied for their positive effects in the prevention or cure of some cancers, cardiovascular disease, age-related diseases, and other disorders.[18-21]
Each antioxidant has individual actions that are often predictable. For example, the enzyme superoxide dismutase reacts with superoxide radicals and protons, as shown below:
2O2 + 2H ® O2 + H2O2
Copper, zinc, and manganese are essential metalloenzymes of superoxide dismutase, which are considered antioxidants when they are incorporated into superoxide dismutase.
The antioxidant enzyme catalase converts hydrogen peroxide to less reactive oxygen and water, according to the following reaction:
2H2O2 ® 2H2O + O2
Catalase requires iron. Yet, iron and copper are among the most common biological oxidant catalysts, which readily transfer electrons to oxygen and, thus, form reactive oxygen species.
Many antioxidant compounds are found in vivo. The normal antioxidant activity derived from dietary sources is usually balanced by free radicals generated from daily stresses, such as inflammation, exercise, detoxification, certain chemicals, radiation, ultraviolet light, alcohol, and fatty diets. This basal level of in vivo antioxidant activity quenches reactive oxygen species and facilitates repair of DNA damage, among other effects.[22]
Predictable Mechanisms of Interaction
Dietary antioxidants can quench free radicals generated from many sources, including chemotherapeutic agents.[23-26] This is the principal mechanism of interaction considered herein affecting agents that utilize reactive oxygen species for their antitumor effect. One free radical removes electrons from stable compounds, thus creating new reactive oxygen species, each with cytotoxic potential.[18] The reaction and associated cytotoxicity continue until stability is attained.
Premature stability can be reached when excess antioxidants interrupt the chain reaction early, thus ending the cytotoxicity of that arm of the reaction.[22,27] Such a reduction in concentration of free radicals generated by chemotherapeutic agents has the same effect as a reduction in dose.[23]
Factors That May Predict Interactions
Existing data provide credible mechanisms for the interaction of certain chemotherapeutic agents and dietary antioxidants. The six factors discussed below are proposed as a basis for predicting interactions between chemo-therapeutic agents and antioxidant compounds (Table 1).
Fraction of Drug Effectiveness That Depends on Reactive Oxygen Species—Many currently available chemotherapeutic agents have more than one suggested mechanism of action, and some do not depend on oxidative mechanisms for cytotoxicity. Alkylators, anthracyclines, and other drug classes that utilize known oxidative mechanisms require attention for potential free radical–antioxidant interactions, whereas many antimetabolites, plant-derived drugs, and other agents whose actions do not include generation of reactive oxygen species are not likely candidates for this reaction.[11-13,16,17] Free radical–antioxidant interactions can be highly specific.[8,22]
Nature of the Reactive Species Generated by the Chemotherapeutic Agent—Different chemotherapeutic agents generate different kinds of free radicals. Protons, oxygen radicals, hydrogen peroxide, and other species have unique interactions with tissue and antioxidant compounds. In addition, the pharmacokinetics of the generated reactive oxygen species warrant consideration. The distribution, metabolism, and excretion sites of metabolites may differ from the parent compound. The timing and half-life of reactive species can be unique as well.
Many chemotherapeutic agents, especially those that must be metabolized to reach their active form, may vary considerably in their effects in different individuals. For example, some patients treated with cyclophosphamide (Cytoxan, Neosar) do not produce carboxyphosphamide and, as a result, produce more than twice the expected levels of highly reactive phosphoramide mustard.[28]
Dosage and Concentration of Reactive Oxygen Species—The specific dosage and concentration of the reactive oxygen species can determine the level of reaction and, to some extent, the clinical response.
It is well known that high-dose chemotherapy regimens can produce better long-term outcomes even when measurable tumor response at the lower dose is considered good. This difference may be due to the fact that the high-dose regimen achieves a more complete cytotoxic response, thus interfering with the ability of tumor cells to mutate to resistant strains. It may also reflect the ability of higher in vivo concentrations to more completely intercept and destroy micrometastases.[14,29,30]
Furthermore, the concentration of reactive oxygen species and its relationship to maximum drug effect determines the extent to which drug-nutrient interactions can interfere with this action. According to the Michaelis-Menten model:
Effect = (Maximal effect × [D]) / (KD + [D])
As drug dose (D) approaches maximum effect, changes in dose have a diminishing impact on effect. Based on this model, low-dose, fractionated regimens would be predicted to be more vulnerable to dosage variations resulting from drug-nutrient interactions.
Nature of the Antioxidant— Since individual antioxidants have specific actions when interacting with reactive oxygen species, the action of the antioxidant can determine whether a reaction is even possible. Moreover, the pharmacokinetics of the antioxidants, in combination with those of the reactive oxygen species, can predict whether the reactants will be in the same place at the same time.
The antioxidant mesna (Mesnex) is an excellent example of this principle. Mesna is rapidly metabolized in vivo to mesna disulfide, which undergoes rapid renal excretion. Its high antioxidant concentration in the renal pathway interacts with the metabolite acrolein, thus limiting the renal toxicity of classical alkylators, such as cyclophosphamide and ifosfamide, without affecting their target cytotoxicity.[16,31]
Concentration of the Antioxidant—Antioxidant activity is a common, necessary part of many normal reactions in the body and is provided in essentially all foods. There is always some antioxidant activity in vivo, including during treatment with chemotherapeutic agents of concern. Antioxidant intake at the levels present during clinical trials should not affect outcome. The concentration of antioxidants, together with the concentration of reactive oxygen species, will determine the level of the reaction, likely according to the Michaelis-Menten model.
Temporal Relationship Between the Antioxidant and ReactiveOxygen Species—The temporal relationship between antioxidant intake and the administration of the chemotherapeutic agent of concern may be the single best factor for predicting or ruling out interactions within this model.[31] There are, however, several caveats:
For drugs that undergo multiple transformations, these specific pharmacokinetic data must be considered, since the product of the first or second transformation may not be the one that is important.
When appropriate, a two-compartment model may be critical, since tissue rather than plasma may be where significant drug-antioxidant interactions are occurring.
The time course of drug effect can be affected dramatically by impaired elimination—a not uncommon problem with this class of agents.
Markedly increasing tissue stores of antioxidants, when that is pos-sible, may affect a drug-antioxidant interaction beyond the period predicted by pharmacokinetics.
Implications for Future Research
In vitro studies investigating the combination of chemotherapeutic agents and antioxidants must be interpreted carefully. Human free radical and antioxidant activity exist in a complex biochemical framework that cannot be duplicated in a petri dish. Considering the number of independent variables, the chances for both false-negativeand false-positive interactions are very high.
New studies should account for the effects of interactions on solitary tumor cells, not just on overt tumor response. Existing models for the antitumor action of agents that generate reactive oxygen species, the ability of antioxidants to reduce the numbers of free radicals, and the relationship between concentration of reactive oxygen species and its effect on micrometastases, as discussed above, clearly suggest that a drug’s ability to destroy micrometastases may be impaired by the addition of antioxidants. Paradoxically, this may result in an improved short-term tolerance to treatment followed by an increased long-term chance for recurrence. For this information to be clinically meaningful, it is critical to examine long-term recurrence and survival rates.
Implications for Clinical Practice
Cancer patients who use nutritional supplements with antioxidant activity risk interfering with actions of chemotherapeutic agents that utilize reactive oxygen species as a mechanism for cytotoxicity. Ironically, these patients may improve their short-term tolerance to treatment while increasing their vulnerability to later recurrence as a result of having decreased the effectiveness of the drug.
Options for the Patient Interested in Nonconventional Therapies
It is suggested that all patients be questioned about their use of medications or nutritional supplements other than those prescribed by the oncologist. When the patient demonstrates an interest in nonconventional care, the busy oncologist has several options:
1. Develop a nonconventional treatment plan based on the pharmacology of the conventional and nonconventional substances. The pharmacodynamics of nutrients that are potent, common sources of oral antioxidant activity, such as vitamins and minerals, are fairly well known and well documented. The pharmacology of the other common source of nonconventional therapies with antioxidant activity, botanicals, is documented in pharmacognosy textbooks, which are part of the syllabuses of many schools of pharmacy. The body of clinical data on “nonconventional” therapies is not extensive as body of knowledge on more recent conventional pharmaceuticals, but the former does exist and is growing rapidly.
In the section below, we suggest a plan for adjunctive nonconventional therapy aimed at avoiding undesired interactions; this plan is based on a available information and prudence. Where adequate data do not exist, we assume that an interaction is possible. As a practical matter, there are sufficient data on the half-life, distribution, elimination and activity of many of the substances on the market to predict their effects.
This option has the advantage of almost certainly ensuring patient compliance but has the disadvantage of being time-consuming and a distraction for the oncologist and staff. A knowledgeable consultant can be asked to develop the nonconventional plan.
2. Instruct the patient to avoid all nonconventional therapies during the period when conventional agents are most vulnerable to interactions, based on standard pharmacokinetics. This option usually generates patient compliance and provides a safety zone. It still uses valuable time but much less than development of an adjunctive plan.
3. Instruct the patient to discontinue all nonconventional nutritional supplementation during the course of anticancer treatment. This option often does not foster patient compliance unless the treatment course is very short. Studies indicate that patients asked to forego nonconventional supplements may surreptitiously use them anyway, very possibly risking undesirable interactions.[1]
Suggested Plan for Adjunctive Nonconventional Treatment
A plan for adjunctive nonconventional therapy can be developed based on the pharmacologic principles discussed above, as well as the identification of the substances vulnerable to interaction. Chemotherapeutic agents with cytotoxic activity known to be dependent on reactive oxygen species are listed in Table 2. These include: classical alkylating agents; anthracycline antitumor antibiotics, such as doxorubicin, daunorubicin (Cerubidine), epirubicin, and idarubicin; mitomycin (Mutamycin); bleomycin (Blenoxane); and the podophyllum class of plant-derived agents, such as etoposide and teniposide (Vumon).
The definitive molecular pharmacology of certain chemotherapeutic agents, such as the antitumor antibiotic plicamycin (Mithracin), as well as some new and investigational drugs, has not been established. Until more is known about these agents, it is suggested that they be treated as though they were capable of interacting with antioxidants.
Hormonal agents, biological agents, antimetabolites, and some plant-derived agents, including the vinca alkaloids and taxanes, have generally demonstrated pharmacologic actions that do not depend primarily on free radical activity (Table 2). These drugs are probably not directly vulnerable to antioxidants. It is still recommended that patients treated with these agents avoid very high levels of antioxidant supplementation until long-term studies are available, since a secondary, uncharted mechanism may still contribute to the action of these drugs.
Most of the nonconventional treatments recommended for use with oncology patients have antioxidant activity. The most common of these include: vitamins A (including beta-carotene), B6, C, and E; minerals, including zinc and selenium; bioflavonoids; superoxide dismutase; glutathione; and most botanical medicines. The antioxidant activity of the botanical medicines has not yet been rigorously calculated. Unless there are specific data to the contrary, it is best to assume that plant and herbal preparations have antioxidant actions.
The clinical objective is to avoid high antioxidant levels while the drug is still active and vulnerable to interference. Utilizing standard oncologic pharmacokinetic resources, drugs with a typical hyperbolic dose-response relationship can be timed four to six half-lives from administration in patients demonstrating normal elimination and metabolism.
Nutrients that have long half-lives and are eliminated according to a two-compartment model, such as vitamin E, may be inappropriate for supplementation with some chemotherapy regimens. This is not an uncommon circumstance. On the other hand, when the half-lives and actions of the nutrients and chemotherapeutics are compatible, sensible programs can be initiated.
There are some special clinical considerations that can be dealt with in accordance with traditional pharmacologic principles. For example, patients with known elimination pathway difficulties, such as renal or hepatic insufficiency, will require more time between administration of chemotherapy and use of supplements. When the drug has a two-compartment or questionable terminal half-life, longer periods will provide a margin of safety.
Drugs that are part of combination therapies may not demonstrate the same pharmacokinetics as single agents. Drugs that exhibit nonhyperbolic dose-response relationships can be calculated utilizing standard pharmacologic methods.
The same information is available for many of the nonconventional treatments in standard pharmacology and pharmacognosy references. If nutritional supplementation above the recommended daily allowance (RDA) is to be allowed for part of the treatment time, the multicompartment distribution and elimination of the nutrients must be considered to ensure that high residual antioxidants do not remain in serum or tissue at the time of treatment. This is especially important with fat-soluble nutrients because of their ability to reside in the tissue for long periods. Patients who use multiple nutrients or who have renal or hepatic insufficiency require special attention.
Warning Signs of Possible Interactions
Clinical warning signs of antioxidant–reactive oxygen species interactions include tolerance to conventional drug administration that is much better or worse than expected, unusual toxic effects from treatment, or unanticipated refractoriness to conventional treatment. Asking the patient about use of alternative therapies can provide clues to otherwise unexplained clinical responses and perhaps avoid an unnecessary treatment failure secondary to this particular adverse interaction.
Conclusions
Is there any actual evidence of antioxidant–chemotherapeutic drug interactions? There are many anecdotes about such interactions. Unfortunately, however, the current reporting system includes no mechanism for monitoring for these interactions. At present, treatment failures are not compared to patients’ use of nonconventional treatments. One the objectives of this article is to increase oncologists’ attention to potential interactions by articulating these mechanisms.
References
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