Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status.

Melatonin (MLT) is the main hormone released from the pineal gland and has proved to have physiological antitumor activity. MLT has been shown to exert anticancer activity through several biological mechanisms: antiproliferative action, stimulation of anticancer immunity, modulation of oncogene expression, and anti-inflammatory, anti-oxidant and anti-angiogenic effects. Several experimental studies have shown that MLT may inhibit cancer cell growth, and preliminary clinical studies seem to confirm its anticancer property in humans. In addition, MLT may have other biological effects, which could be useful in the palliative therapy of cancer, namely anticachectic, anti-asthenic and thrombopoietic activities. On this basis, the present clinical investigation was performed in an attempt at better definition of the therapeutic properties of MLT in human neoplasms. In a first clinical study, we evaluated the effects of MLT in a group of 1,440 patients with untreatable advanced solid tumors, who received supportive care alone or supportive care plus MLT. In a second study, we evaluated the influence of MLT on the efficacy and toxicity of chemotherapy in a group of 200 metastatic patients with chemotherapy-resistant tumor histotype, who were randomized to receive chemotherapy alone or chemotherapy plus MLT. In both studies, MLT was given orally at 20 mg/day during the dark period of the day. The frequency of cachexia, asthenia, thrombocytopenia and lymphocytopenia was significantly lower in patients treated with MLT than in those who received supportive care alone. Moreover, the percentage of patients with disease stabilization and the percentage 1-year survival were both significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone. The objective tumor response rate was significantly higher in patients treated with chemotherapy plus MLT than in those treated with chemotherapy alone. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity and neurotoxicity. These clinical results demonstrate that the pineal hormone MLT may be successfully administered in medical oncology in the supportive care of untreatable advanced cancer patients and for the prevention of chemotherapy-induced toxicity.

Is there a role for melatonin in supportive care

Recent observations have shown that the pineal hormone melatonin (MLT) may modulate oestrogen receptor (ER) expression and inhibit breast cancer cell growth. On this basis, we have evaluated the biological and clinical effects of a concomitant MLT therapy in women with metastatic breast cancer who had progressed in response to tamoxifen (TMX) alone. The study included 14 patients with metastasis who did not respond (n = 3) to therapy with TMX alone or progressed after initial stable disease (SD) (n = 11). MLT was given orally at 20 mg day-1 in the evening, every day starting 7 days before TMX, which was given orally at 20 mg day-1 at noon. A partial response was achieved in 4/14 (28.5%) patients (median duration 8 months). The treatment was well tolerated in all cases, and no MLT-induced enhancement of TMX toxicity was seen; on the contrary, most patients experienced a relief of anxiety. Mean serum levels of insulin-like growth factor 1 (IGF-1), which is a growth factor for breast cancer, significantly decreased on therapy, and this decline was significantly higher in responders than in patients with SD or progression. This pilot phase II study would suggest that the concomitant administration of the pineal hormone MLT may induce objective tumour regressions in metastatic breast cancer patients refractory to TMX alone.

Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone

Is there a role for melatonin in the treatment of neoplastic cachexia

EFFECT OF MELATONIN ON NF‐κB DNA‐BINDING ACTIVITY IN THE RAT SPLEEN

Melatonin (5-methoxy-N-acetyltryptamine) is a lipidsoluble derivative of 5-hydroxytryptamine, which is produced clinically via the pineal gland under the influence of sympathetic neural tone governed by diurnal variation in light exposure. Melatonin secretion is maximal with the onset of darkness and it controls diurnal rhythms (i.e., temperature and sleep) and the seasonal Zeitgebar involving reproductive behavior, the seasonal pelt, and pigmentation. The complicated patterns of these relationships between pituitary-hypophyseal, light exposure, and the pineal gland that may be mediated by melatonin have been discussed in a number of reviews (1-13). These observations have resulted in a recent conference on melatonin in humans (14) where melatonin diurnal and seasonal rhythms have been shown to be a factor in sleep and seasonal affective disorders. Recent observations suggest that melatonin deserves clinical trial to enhance or modify response in hormonally sensitive tumors and to determine if melatonin’s impact on chronobiologic control can improve the circadian

Melatonin: a rediscovered antitumor hormone? Its relation to surface receptors; sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy.

W. Pierpaoli

Papers

Melatonin: a rediscovered antitumor hormone? Its relation to surface receptors; sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy.