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Life Extension Magazine

LE Magazine January 2004
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Melatonin and Cancer Treatment
By Eileen M. Lynch, PhDOncology Research Scientist

Melatonin and Cancer Surgery
In peri- and post-operative cancer surgery, melatonin may prove beneficial in wound healing through its natural anti-inflammatory properties.14,59 Melatonin reduces tissue destruction during inflammatory reactions60 by limiting hypoxia-reoxygenation-induced damage,61 scavenging free radicals, and reducing the upregulation of pro-inflammatory cytokines,60 such as the interleukins and tumor necrosis factor-alpha. Furthermore, surgery induces immunosuppression, which could adversely affect tumor-host interactions in cancer patients having their tumors surgically removed. As melatonin inhibits the activation of the acute inflammatory response, it may inhibit immunosuppression while contributing to an immune reaction against the tumor.14 Moreover, melatonin can reverse the perception of pain sensation (hyperalgesia) that is secondary to inflammation associated with wound healing.56

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
Radiation requires the presence of oxygen to generate free radicals to kill tumor cells. It is well established, however, that most human tumors are poorly oxygenated (hypoxic) because of blood perfusion and diffusion limitations,62 intermittent blood flow in the tumor microcirculation,63 and the occurrence of anemia in cancer patients (reduced hemoglobin indicates reduced oxygen levels).64,65 In fact, radiation therapy itself usually induces anemia, which is associated with a poor prognosis in cancer patients.66 Melatonin stimulates platelet production (thrombopoiesis)67 and has been shown to effectively treat cancer patients with low platelet counts and anemia.68

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.

Summary of Studies Using Melatonin
Lissoni’s Phase II Randomized Clinical Trial Results

       

One-Year Survival

 

Tumor Type

Patient Number

Basic Therapy

Melatonin Dose

Melatonin

Placebo

Level Of Significance

Metastatic Non- Small-Cell Lung

100

Chemotherapy

20 mg

5-year survival 6%

5-year survival 0%

N/A

Metastatic Non- Small-Cell Lung

63

Supportive Care Only

10 mg

5-year survival 6%

Under 1%

<0.05

Glioblastoma

30

Conventional Radiotherapy

10 mg

43%

Under 1%

<0.05

Metastatic Breast

14

Tamoxifen

20 mg

64%

36%

<0.01

Brain Metastases

50

Conventional Radiotherapy

20 mg

38%

12%

<0.05

Metastatic Colorecta

50

IL-2

40 mg

36%

12%

<0.05<0.05

Metastatic Non- Small-Cell Lung

60

IL-2

40 mg

24%

19%

<0.05

Adapted from Life Extension (March 2002). Originally compiled by Cancer Treatment Centers of America.

Melatonin and Chemotherapy
Chemotherapy, through immunosuppressive and cytotoxic actions, exerts detrimental effects on patients’ physiological anti-cancer defense mechanisms. Melatonin, by improving immune status,52,75 has been shown to prolong survival and increase performance status in those undergoing chemotherapy. In conjunction with various chemotherapy regimens, melatonin has provided patients with a significant advantage over chemotherapy alone by increasing five-year survival rates, improving quality of life, and increasing the therapeutic effectiveness of many chemotherapeutic agents,76 while lessening or eliminating their negative and potentially detrimental side effects on normal healthy cells and tissues.4,77,78 Melatonin reduced chemotherapy-induced cardiotoxicity, neurotoxicity, nephrotoxicity, thrombocytopenia (reduced platelet counts), stomatitis (inflammation of mouth), and asthenia (weakness), and improved response in cancer patients.79,80

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
Because of the circadian rhythm dictated by the body’s melatonin levels, some types of chemotherapy work best if administered at an appropriate time of day, and are thus termed “chronotherapy.”3 The daily rhythm of melatonin exerts a “chronobiotic” effect and, as a circadian mediator, melatonin delivers the circadian signals to melatonin targets, including the internal body clock (in the suprachiasmatic nucleus).85 Chronotherapy is associated with maximum patient tolerability, tumor susceptibility, and attempts to improve the efficacy of treatment and the quality of patients’ lives. It takes advantage of asynchronies in growth rate between normal and tumor cells that are regulated by the circadian rhythm, thus minimizing damage to the patient and maximizing drug toxicity to tumor cells.

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

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