Antioxidants in Cancer Therapy; Their Actions and Interactions With Oncologic Therapies
By Davis W. Lamson, MS, ND and Matthew S. Brignall, ND
Abstract
There is a concern that antioxidants might reduce oxidizing free radicals created by radiotherapy and some forms of chemotherapy, and thereby decrease the effectiveness of the therapy. The question has arisen whether concurrent administration of oral antioxidants is contraindicated during cancer therapeutics. Evidence reviewed here demonstrates exogenous antioxidants alone produce beneficial effects in various cancers, and except for a few specific cases, animal and human studies demonstrate no reduction of efficacy of chemotherapy or radiation when given with antioxidants. In fact, considerable data exists showing increased effectiveness of many cancer therapeutic agents, as well as a decrease in adverse effects, when given concurrently with antioxidants. Altern Med Rev 1999;4(5):304-329
Introduction
Dietary and endogenous antioxidants prevent cellular damage by reacting with and eliminating oxidizing free radicals. However, in cancer treatment, a mode of action of certain chemotherapeutic agents involves the generation of free radicals to cause cellular damage and necrosis of malignant cells. So a concern has logically developed as to whether exogenous antioxidant compounds taken concurrently during chemotherapy could reduce the beneficial effect of chemotherapy on malignant cells. The importance of this concern is underlined by a recent study which estimates 23 percent of cancer patients take antioxidants.1
The study of antioxidant use in cancer treatment is a rapidly evolving area. Antioxidants have been extensively studied for their ability to prevent cancer in humans.2 This paper reviews the use of antioxidants as a therapeutic intervention in cancer patients, and their potential interactions with radiation and chemotherapy. There has been significant investigation of this area, with promising findings which indicate continuing investigation is warranted. For further discussion of the use of antioxidants as sole cancer therapy, refer to the review article by Prasad published earlier this year.3 A number of reports show a reduction in adverse effects of chemotherapy when given concurrently with antioxidants. These data are more completely summarized by Weijl et al.4
Conflicting Views of Antioxidant Use in Cancer Therapy
It was suggested in a recent publication that no supplementary antioxidants be given concurrently with chemotherapy agents which employ a free radical mechanism.5 The paper must be commended for pointing out that the combination of antioxidants and chemotherapy agents needs more investigation, and should serve as a wake-up call regarding how much we need further definition of the actions of specific antioxidants with chemotherapeutic agents. However, it should not serve as scientific closure on an adjunctive treatment of possible great promise in cancer therapy.
The present authors are by no means recommending any lack of caution about use of antioxidants. On the contrary, published research indicates the cautious and judicious use of a number of antioxidants can be helpful in the treatment of cancer; as sole agents and as adjuncts to standard radiation and chemotherapy protocols.
It was suggested that antioxidants might interfere with the oxidative mechanisms of alkylating agents.5 These drugs create substantial DNA damage, resulting in cell necrosis. However, recent evidence indicates a sizeable amount of chemotherapy damage is by other mechanisms, which trigger apoptosis.6 Antioxidants have been shown to increase cell death by this mechanism.7,8 Given this, any argument that antioxidants are likely to interfere with most chemotherapy is too simplistic and probably untrue.
Numerous animal studies have been published demonstrating decreased tumor size and/or increased longevity with the combination of chemotherapy and antioxidants.7,9-16 A recent study was conducted on small-cell lung cancer in humans using combination chemotherapy of cyclophosphamide, Adriamycin (doxorubicin), and vincristine with radiation and a combination of antioxidants, vitamins, trace elements, and fatty acids. The conclusion was "antioxidant treatment, in combination with chemotherapy and irradiation, prolonged the survival time of patients" compared to expected outcome without the composite oral therapy.17 Two human studies found melatonin plus chemotherapy to induce greater tumor response than chemotherapy alone.18,19 The treatments producing these positive results would have been advised against by those advocating no antioxidant use during chemotherapy. These studies will be discussed in more detail below.
It is the opinion of the authors of this paper that interactions between antioxidants and chemotherapeutics cannot be predicted solely on the basis of presumed mechanism of action. The fact remains that physicians must be aware of the available research to help their patients take advantage of positive interactions existing between antioxidants and chemotherapy or radiation.
Additionally, physicians need to remain aware of the large body of evidence showing a positive effect of antioxidants in the period following chemotherapy administration. The general protocol with standard oncologic therapies is to follow a watch-and-wait strategy after therapeutic administration is concluded. This is a period when supplemental therapies are highly indicated and have been demonstrated to result in a higher percentage of successful outcomes.20,21
Overview of Cancer Therapeutic Agents
Chemotherapy agents can be divided into several categories: alkylating agents (e.g., cyclophosphamide, ifosfamide), antibiotics which affect nucleic acids (e.g., doxorubicin, bleomycin), platinum compounds (e.g., cisplatin), mitotic inhibitors (e.g., vincristine), antimetabolites (e.g., 5-fluorouracil), camptothecin derivatives (e.g., topotecan), biological response modifiers (e.g., interferon), and hormone therapies (e.g., tamoxifen).The agents most noted for creating cellular damage by initiating free radical oxidants are the alkylating agents, the tumor antibiotics, and the platinum compounds. The agents in these categories demand definition concerning interactions with antioxidants which might reduce effectiveness of chemotherapy. There is also the possibility of adverse interaction between antioxidant treatment and agents that do not act via an oxidative mechanism (e.g., 5-fluorouracil or tamoxifen).
In addition to the idea that chemotherapy must create a lethal injury to DNA to produce malignant cell death is the mechanism of apoptosis. A dose of chemotherapy which does not produce necrosis can trigger apoptosis, either immediate or delayed. Additionally, anti-apoptotic mutations can result in drug resistance in human tumors. At least one antioxidant (quercetin) has been demonstrated to overcome such an anti-apoptotic blockage.22
Radiotherapy uses ionizing radiation to produce cell death through free radical formation. Two mechanisms are involved. The apoptosis mechanism results in cell death within a few hours of radiation. The second mechanism is radiation-induced failure of mitosis and the inhibition of cellular proliferation, which kills cancer cells. Currently, the principal target of radiation is considered to be cellular DNA. However, studies show the signal for apoptosis can be generated by the effect of radiation on cell membranes, apparently through lipid peroxidation. This suggests an alternate mechanism to the hypothesis that DNA damage is required for cell death.23
Combinations of Antioxidants
Given that many antioxidants have been shown to have anti-tumor properties, it is worth exploring their use in combination. A study in mice found co-administration of beta-carotene and alpha-tocopherol led to much greater tumor regression than either agent alone. The effect was synergistic, being much greater than the sum of the mild tumor inhibition of beta-carotene and alpha-tocopherol.174 Other studies have shown multivitamin supplements were associated with fewer recurrences of solid tumors after remission following standard oncologic therapies.20,21
A small double-blind trial of a mixture of antioxidants, including 600 mg vitamin E, 1 g vitamin C, and 200 mg NAC taken only during treatment, looked at the potential of this mixture to prevent cardiotoxicity during chemo- and radiotherapy. No patient taking the antioxidant mixture had a fall in ejection fraction greater than 10 percent. In patients taking placebo, four of six patients undergoing radiotherapy and two of seven patients treated with chemotherapy had an ejection fraction reduction of 10 percent or more. Treatment outcomes in patients taking antioxidants versus placebo were not discussed.175
An open trial of combination antioxidant treatment along with chemotherapy and radiation in patients with small-cell lung cancer had encouraging results. Patients taking the supplement, which contained at least 15,000 IU vitamin A, 10,000 IU beta-carotene, 300 IU alpha-tocopherol, 2 g vitamin C, and 800 mcg selenium, were able to tolerate chemotherapy and radiation well. Their two-year survival rate was greater than that of historical controls (>33% to <15%), survivors =" 32">Current Attitudes and New Approaches to Treatment
Cancer therapy has been remarkably consistent for the last 50 years. Surgery, radiation, and chemotherapy have been the cornerstones of conventional treatment. Not surprisingly, the clinical success of these treatments has reached a plateau.176 Some authors have even questioned the validity of chemotherapy as a treatment for most cancers.177 Clearly, there is a need for new therapies which can increase the efficacy of cancer treatment. Careful application of antioxidants may be a means helping to raise cancer therapy to a new level of success.4
The attitude of many conventional practitioners toward antioxidant therapy for cancer has been hostile.178 Others have raised the argument that antioxidants could blunt the effect of standard therapies, particularly alkylating, platinum, and tumor antibiotic agents, which are oxidative in nature.5 While this appears a theoretical concern, the evidence reviewed here shows that this proposed interaction of anti- and pro-oxidant therapies is not generally of primary importance in vivo. It is time to put this argument in perspective.
Potential Mechanisms of Antioxidants in Cancer Therapy
How could antioxidant therapy protect normal cells against damage from cancer therapies, while often increasing their cytotoxic effect against malignant cells? While the answer to this question is not entirely mapped out, there are concepts which might help us understand. One is the recent evidence that radiation and chemotherapy often harm DNA to a relatively minor extent, which causes the cells to undergo apoptosis, rather than necrosis.6 Since many antioxidant treatments stimulate apoptotic pathways,7,8 the potential exists for a synergistic effect with radiation or chemotherapy with antioxidants.
A second concept is that the defensive mechanisms of many cancer cells are known to be impaired. This presumably makes tumor cells unable to use the extra antioxidants in a repair capacity; this has been illustrated in vitro. An experimental murine ascites tumor cell line was found to have 10 -100 times less catalase than comparable normal cells. This led to a build-up of hydrogen peroxide in the cells upon treatment with vitamin C, in turn leading to cell death. The cytotoxic effects of vitamin C were completely eliminated by addition of catalase to the cell culture.179 Since publication of these findings, most human tumor cell lines studied have proved to be similarly low in catalase.180
Caveats When Considering Using Antioxidants in Cancer Treatment
We wish to emphasize three concerns regarding the use of antioxidants raised in this paper. One is the routine use of N-acetylcysteine with certain chemotherapeutic agents, namely cisplatinum and doxorubicin. Given the limited therapeutic benefits associated with NAC in cancer treatment, and the number of other antioxidants shown above to help reduce the toxicities of these two chemotherapeutic agents, there appears little reason to consider NAC a first-line adjunct with either agent. Since the potential for adverse interaction with chemotherapy appears to be greater with NAC, perhaps it should be used only in situations where it has clearly been shown to not interfere with other therapies.
The second concern we wish to reiterate is the interaction between tangeretin and tamoxifen. Except in cases where interactions with specific flavonoids are clearly defined, it seems prudent to avoid treatment with flavonoids in therapeutic doses concurrently with tamoxifen. It is unknown currently if there is any reduction in tamoxifen activity associated with dietary flavonoids, which are ubiquitous in the plant kingdom.
The third area of concern is the potential reduction of 5-fluorouracil (5-FU) activity by beta-carotene.58The nature of this interaction is not clear. Until this is clarified, the combination would best be avoided.
Conclusion
Frequently, the effects of using antioxidants concurrent with chemotherapy and radiation are synergistic. Except for three specific interactions outlined above (flavonoids with tamoxifen, NAC with doxorubicin, and beta-carotene with 5-fluorouracil), there is no evidence to date showing that natural antioxidants interfere with conventional cancer therapeutics in vivo. Studies have shown patients treated with antioxidants, with or without chemotherapy and radiation, have many benefits. Patients have been noted to tolerate standard treatment better, experience less weight loss, have a better quality of life, and most importantly, live longer than patients receiving no supplements. It is time to research the role of these agents in conventional oncologic treatment, rather than dismiss them as a class based on theoretical concerns.
Comment: I would like to thank these Doctors for the research they did here. In putting this blog together, I did not use all of the research paper in my blog, but do recommend that anyone that is seeking advise on this issue, view the whole document. You may read the research paper in it's entirety at thorne.com
CW
Christopher Wiechert's Healthblogger is for educational or informational purposes only, and is not intended to diagnose or provide treatment for any condition. If you have any concerns about your own health, you should always consult with a healthcare professional. If you decide to use this information on your own, it's your constitutional right, but I assume no responsibility.
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