222016Jan
Is the Antioxidant Melatonin Dangerous during Chemotherapy and Radiation?

Is the Antioxidant Melatonin Dangerous during Chemotherapy and Radiation?

Written By: Dr. Adam McLeod, ND, BSc (Hons)

It is not unusual for patients to be intimidated by their medical oncologists to fear all natural therapies. They are told to specifically avoid all antioxidants because they will neutralize the effects of chemotherapy and radiation. This broad generalization that all antioxidants should be avoided is simply not supported by scientific evidence. On an intuitive level, it makes sense that if chemotherapy is creating oxidative damage as its mechanism of action then providing the body with antioxidants would theoretically neutralize this mechanism. There are legitimate concerns with specific chemotherapies and high doses of synthetic antioxidants. However, there are many double blind human trials which demonstrate that antioxidant supplementation at moderate doses decreases side effects without interfering with the effects of the chemotherapy12,13,14. There is also no debating that patients who consume natural sources of antioxidants respond better to chemotherapy and radiation with less side effects33,7. If antioxidants are to be feared, then why do patients with better antioxidant capacity in their blood respond better to these conventional therapies?

There are several things which must be considered. First of all this simplistic view that all antioxidants are bad has long been debunked and this is not supported in the scientific literature31. Secondly, not all chemotherapies work by creating oxidative damage so the argument against antioxidants in these cases is nonsense. Another important point is that antioxidants can help your healthy cells to recover from the residual toxic effects of chemotherapy28,29,30. To add to the hypocrisy of the “avoid all antioxidant stance”, it is not unusual for oncologists to administer powerful pharmaceutical antioxidants such as theophylline to reduce side effects from chemotherapy34.

The antioxidant capacity of your blood is a measure of how effectively your blood is capable of neutralizing free radicals. The consumption of antioxidant rich foods dramatically increases the concentration of antioxidants in the blood which consequently increases antioxidant capacity3. It is well known that patients who have lower antioxidant capacity in their blood have greater side effects to chemotherapy32.

The notion that all medical oncologists share this view of fearing antioxidants is simply not true. There are major integrative cancer centres in the US where naturopathic doctors work along-side medical oncologists and things like melatonin and Vitamin C are given as standard therapies to patients undergoing chemotherapy or radiation. Of course there are specific interactions that must be avoided and a Naturopathic Doctor who is skilled in oncology will be able to guide you to develop a safe and effective plan. You must have professional guidance when developing a treatment plan in the complicated clinical context of cancer.

One of the most common natural therapies given to patients undergoing chemotherapy is melatonin. I have heard on numerous occasions from patients who were warned from the cancer agency pharmacist that melatonin is contraindicated during chemotherapy and radiation because it is an antioxidant. What I find so bizarre about this statement is that virtually all of the available scientific literature literally says the opposite and strongly supports the use of melatonin with chemotherapy and radiation. The position of scaring patients about melatonin is not grounded in scientific evidence, they take this position because from a legal perspective it is easier to say avoid any and all antioxidants.

What does the research say about melatonin used in combination with chemotherapy? Several randomized double blind trials have tested patients with lung cancer who were treated with chemotherapy alone or chemotherapy in combination with melatonin. The melatonin group not only lived longer they also had significantly better quality of life when compared to the group not given melatonin15,16,17. Melatonin has been consistently shown to enhance the effects of chemotherapy while reducing side effects18,19,20,25. It is however important to point out that not all cancers are the same and melatonin is not indicated for all cancers. In fact, it is contraindicated with many blood cancers such as leukemia.

What does the scientific literature actually say about combining melatonin with radiation therapy? Patients who concurrently take melatonin during radiation therapy for glioblastoma live significantly longer than those who just received radiation therapy21. Melatonin helps to protect damage to the immune system during radiation22,23,24. Although melatonin is a well documented antioxidant, there are numerous studies which demonstrate that melatonin actually makes cancer cells more sensitive to the effects of radiation26,27.

When used appropriately certain antioxidants such as melatonin can reduce side effects from conventional cancer therapies without interfering with their effectiveness. Healthy cells need antioxidants too and when you consume natural sources of antioxidants the net effect is that it protects healthy cells much more than cancer cells. Ultimately this makes the drugs work just as well and the healthy cells are less damaged from the drug. When you consume a diet rich in antioxidants, the antioxidant capacity of your blood increases dramatically and the research clearly demonstrates that this is a good thing during chemotherapy and radiation.

Lets take a moment to look at the data about melatonin and its activity as an antioxidant. After consuming 80mg of melatonin the serum levels peak at approximately 100,000 pg/mL before rapidly dropping by the end of the day2. The standard dose of melatonin given during chemotherapy or radiation is 20mg. Based on this number it is fair to assume that the amount of melatonin in the blood would be approximately 25,000 pg/mL. At first glance this seems like a shockingly high number. It is well documented that when patients eat a diet high in antioxidant rich foods, that the antioxidant capacity of their blood increases and some of this is due to the melatonin in the food3. In one well controlled study after consuming approximately 1L of orange juice the participants had serum melatonin levels rise from 40 to 150 pg/mL1. This is still 150 times less than values that would be expected after consuming 20mg of melatonin.

The data must be taken into the proper context. True antioxidant capacity in the blood is never determined by one single molecule. It is the entire antioxidant network that gives the blood the capacity to neutralize free radicals. There is a potent synergy between hundreds of different antioxidants which counteracts oxidative damage in a balanced way. Each molecule on its own is only one small piece of the complicated antioxidant network. The mechanism by which melatonin neutralizes free radicals is very different from that of Vitamin C and Vitamin E5. Melatonin is often described in the literature as a terminal antioxidant which distinguishes itself from so called opportunistic antioxidants. The bottom line is that the addition of a single antioxidant does not necessarily impact the entire antioxidant capacity of the blood in a linear fashion.

This next section is a bit heavy in math but I feel that it is important to break down these details. Melatonin is approximately 2.04 times more potent of an antioxidant than a molecule called Trolox. This molecule Trolox is often used as a standard to measure the antioxidant capacity in the blood. Blueberries, which are best known for their antioxidant capacity have an ORAC value of 6552. This means that 100g of blueberries will have the same antioxidant capacity as 6552 micromoles of Trolox. Based on this information it is easy to calculate that 15.26mg of blueberries is the equivalent antioxidant capacity of 1 micromol of Trolox. If you convert these values to make it relevant to melatonin, each mg of melatonin is equivalent to 31.13g of blueberries. The standard dose of 20mg of melatonin during chemotherapy is the equivalent of a patient eating 622.71g of blueberries. In other words, if you eat a little over 1 pound of blueberries this should have the equivalent antioxidant effect as 20mg of melatonin.

There is no evidence to suggest that antioxidants from natural sources are dangerous during chemotherapy or radiation. In fact, virtually all of the literature clearly states that it is beneficial to get antioxidants from natural sources. By consuming antioxidant rich foods, patients have fewer side effects during conventional cancer treatments. Many studies have also clearly demonstrated that these foods do not interfere with the effectiveness of these therapies6,7,8,9,10,11. The debate is around synthetic supplementation with high doses of antioxidants during chemotherapy and radiation. Natural sources are well established as beneficial in these cases, as they protect healthy cells without interfering with the effects of conventional therapies9.

Blueberries are a great source of nutrients and they provide a balanced antioxidant support that is synergistic with chemotherapy and radiation. What is particularly interesting is that wild blueberries are much more effective at neutralizing free radicals than cultivated blueberries. Depending on which measurements you use, in some cases the wild blueberries have almost double the antioxidant capacity. So make sure you eat your blueberries and give your cells the nutrients they need!

Dr. Adam McLeod is a Naturopathic Doctor (ND), BSc. (Hon) Molecular biology, Motivational Speaker and International Best Selling Author. He currently practices at his clinic in Vancouver, British Columbia where he focuses on integrative oncology. http://www.yaletownnaturopathic.com

References:

1) Sae‐Teaw, Manit, et al. “Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers.” Journal of pineal research 55.1 (2013): 58-64.

2) Waldhauser, Franz, et al. “Bioavailability of oral melatonin in humans.” Neuroendocrinology 39.4 (1984): 307-313.

3) Cao, Guohua, et al. “Increases in human plasma antioxidant capacity after consumption of controlled diets high in fruit and vegetables.” The American journal of clinical nutrition 68.5 (1998): 1081-1087.

4) Pieri, Carlo, et al. “Melatonin: a peroxyl radical scavenger more effective than vitamin E.” Life sciences 55.15 (1994): PL271-PL276.

5) Tan, D-X., et al. “Significance of melatonin in antioxidative defense system: reactions and products.” Neurosignals 9.3-4 (2000): 137-159.

6) Moss, Ralph W. “Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants?.” Integrative cancer therapies 5.1 (2006): 63-82.

7) Simone, Charles B., et al. “Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1.” Alternative therapies in health and medicine 13.1 (2007): 22.

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11) Block, Keith I., et al. “Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials.” International Journal of Cancer 123.6 (2008): 1227-1239.

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13) Drisko, Jeanne A., Julia Chapman, and Verda J. Hunter. “The use of antioxidant therapies during chemotherapy.” Gynecologic oncology 88.3 (2003): 434-439.

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15) Lissoni, P., et al. “Five years survival in metastatic non‐small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial.” Journal of pineal research 35.1 (2003): 12-15.

16) Lissoni, P., et al. “A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer.” Tumori 80.6 (1994): 464-467.

17) Lissoni, P., et al. “Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin.” Oncology 49.5 (1992): 336-339.

18) Govender, Jenelle, Ben Loos, and Anna-Mart Engelbrecht. “Melatonin: a protective role against doxorubicin-induced cardiotoxicity.” Future Oncology 11.14 (2015): 2003-2006.

19) Tavakoli, Maryam. “Kidney protective effects of melatonin.” Journal of Nephropharmacology 3.1 (2015).

20) Mills, Edward, et al. “Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta‐analysis.” Journal of pineal research 39.4 (2005): 360-366.

21) Lissoni, P., et al. “Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone.” Oncology 53.1 (1996): 43-46.

22) Thomas, Charles R., Russel J. Reiter, and Terence S. Herman. “Melatonin: from basic research to cancer treatment clinics.” Journal of Clinical Oncology 20.10 (2002): 2575-2601.

23) Srinivasan, Venkataramanujan, et al. “Therapeutic actions of melatonin in cancer: possible mechanisms.” Integrative Cancer Therapies 7.3 (2008): 189-203.

24) Blask, David E., Leonard A. Sauer, and Robert T. Dauchy. “Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.” Current topics in medicinal chemistry 2.2 (2002): 113-132.

25) Conti, Ario, and Georges JM Maestroni. “The clinical neuroimmunotherapeutic role of melatonin in oncology.” Journal of pineal research 19.3 (1995): 103-110.

26) Alonso‐González, Carolina, et al. “Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double‐strand DNA break repair.” Journal of pineal research 58.2 (2015): 189-197.

27) Alonso-González, Carolina, et al. “Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis.” Cancer letters 370.1 (2016): 145-152.

28) Ladas, Elena J., et al. “Antioxidants and cancer therapy: a systematic review.” Journal of clinical oncology 22.3 (2004): 517-528.

29) Kasapović, Jelena, et al. “Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages after chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide.” Clinical biochemistry 43.16 (2010): 1287-1293.

30) Chen, Yumin, et al. “Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues.” Molecular interventions 7.3 (2007): 147.

31) Moss, Ralph W. “Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants?.” Integrative cancer therapies 5.1 (2006): 63-82.

32) Kennedy, Deborah D., et al. “Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia.” The American journal of clinical nutrition 79.6 (2004): 1029-1036.

33) Russo, Gian Luigi. “Ins and outs of dietary phytochemicals in cancer chemoprevention.” Biochemical Pharmacology 74.4 (2007): 533-544.

34) Benoehr, Peter, et al. “Nephroprotection by theophylline in patients with cisplatin chemotherapy: a randomized, single-blinded, placebo-controlled trial.” Journal of the American Society of Nephrology 16.2 (2005): 452-458.




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