Melatonin and Cancer Treatment
Oncology Research ScientistJanuary 2004
By Eileen M. Lynch, PhD
Melatonin and Cancer Surgery
In cancer patients undergoing surgical removal of gastrointestinal tract tumors, preoperative neuroimmunotherapy with melatonin and interleukin-2 (IL-2) was capable of neutralizing the surgery-induced reduction in white blood cell counts (lymphocytopenia).14 Melatonin thus may prove to be beneficial to cancer patients who elect surgical removal of their tumors, by improving wound healing, inhibiting tissue damage, reducing pain sensation and weakness, counteracting reduced blood cell counts and anemia, and preventing immunosuppression.
Melatonin and Radiation Therapy
Moreover, melatonin has an anti-serotonergic effect, which means that it may block the inhibition of blood flow by serotonin.26 This consequently may increase blood flow and allow restoration of the microcirculation, which is compromised in the tumor microenvironment.69 Melatonin may improve the blood supply to the tumor, increasing tumor oxygen levels and thus increasing radiation-induced tumor cell death (by overcoming radio-resistance).70 In addition, melatonin is lipid soluble and can presumably cross the blood-tumor barrier as it does the blood-brain barrier.71 Melatonin may further increase the delivery of radiation (and chemotherapeutic drugs) to poorly oxygenated regions within the tumor microenvironment, consequently increasing the effectiveness of these anti-cancer modalities. Radiation, which frequently causes inflammation of the mucosa (mucositis), may substantially reduce melatonin levels in the body13 by damaging the mucosa of the gastrointestinal tract where melatonin is known to be localized.26
A radioneuroendocrine approach utilizing radiotherapy with melatonin supplementation in brain glioblastoma patients showed that the likelihood of survival at one year was significantly higher in those who received melatonin with radiotherapy versus radiotherapy alone.12 It recently has been suggested that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia.72 Therefore, melatonin supplementation may prolong the survival of patients undergoing radiotherapy.3 Melatonin also may provide relief from the inherent detrimental side effects of radiation treatment73 (including toxicity to the heart, kidneys, and nerves—cardiotoxicity, nephrotoxicity, and neurotoxicity, respectively), immune suppression, pain, anemia, fatigue, and sleep disturbances.12 Melatonin is a safe and effective facilitator of tissue repair processes, required for recovery from radiation-induced injury,74 and thus offers a promising co-treatment approach for patients undergoing radiation therapy for cancer.
Melatonin and Chemotherapy
Melatonin should be seriously considered in combination with extremely toxic chemotherapy regimes—such as anthracyclines (adriamycin),81 cyclosporine, cytarabine,78 IL-2, cisplatin,55,79 5-fluorouracil,75,82 and methotrexate78,82—to reduce the incidence of their well-established side effects,80 which include but are not limited to mucositis and heart and liver toxicity.75 Melatonin recently has been shown to prevent methotrexate-induced liver and kidney toxicity in animals.83 It should be remembered that fasting reduces melatonin levels, typically within two days,84 suggesting that nausea, vomiting, and reduced appetite—side effects of chemotherapy—may reduce melatonin levels.
Melatonin and Chronotherapy
The growth of tumor cells may intrinsically follow a tumor-specific rhythm. It may be possible to modulate this rhythm by manipulating cancer patients’ melatonin levels.86 The local effect produced on the circadian clock could thus modulate the circadian rhythm.87 Slow-growing tumors could more likely be controlled by the patients’ circadian clock, whereas fast-growing or advanced-stage tumors may have altered circadian rhythms even though they are not temporally disorganized masses. High doses of melatonin are necessary to induce a phase-shifting effect on the circadian rhythm.88 Melatonin thus may have a unique ability to control the biological clock, consequently suppressing malignant growth and increasing the efficacy of cancer therapies. Chronotherapy has been shown to increase the survival time in children with acute lymphoblastic leukemia.89