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March 2002

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A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms.

BACKGROUND. Unresectable brain metastases remain an untreatable disease. Because of its antitumor cytostatic action and its anticonvulsant effect, the pineal hormone melatonin could constitute a new effective agent in the treatment of brain metastases. The current study was performed to evaluate the effect of melatonin on the survival time in patients with brain metastases due to solid neoplasms. METHODS. The study included 50 patients, who were randomized to be treated with supportive care alone (steroids plus anticonvulsant agents) or with supportive care plus melatonin (20 mg/day at 8:00 p.m. orally). RESULTS. The survival at 1 year, free-from-brain-progression period, and mean survival time were significantly higher in patients treated with melatonin than in those who received the supportive care alone. Conversely, steroid-induced metabolic and infective complications were significantly more frequent in patients treated with supportive care alone than in those concomitantly treated with melatonin. CONCLUSIONS. The pineal hormone melatonin may be able to improve the survival time and the quality of life in patients with brain metastases due to solid tumors.

Cancer 1994 Feb 1;73(3):699-701

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

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 tumor regressions in metastatic breast cancer patients refractory to TMX alone.

Br J Cancer 1995 Apr;71(4):854-6

Interleukin-2, melatonin and interleukin-12 as a possible neuroimmune combination in the biotherapy of cancer.

Suppressive events induced by macrophages and TH2 lymphocytes would represent the most important factors responsible for the in vivo reduced efficacy of IL-2 cancer immunotherapy. Previous studies have shown that IL-3 or the pineal hormone MLT may abrogate macrophage-related suppressive events during IL-2 immunotherapy, while TH2-mediated immunosuppression is not neutralized by MLT or IL-3. On the basis of previous experimental data suggesting the inhibitory effect of IL-12 on TH2 activation, this preliminary study has been performed in an attempt to evaluate the influence of IL-12 on TH2 stimulation induced by IL-2 alone or IL-2 plus MLT, by evaluating the release of IL-10, which represents the main suppressive factor produced by TH2 lymphocytes. Pure lymphocyte cultures were incubated for 4 days with IL-2 (100 Cetus U/ml), MLT (100 pg/ml), IL-12 (1 ng/ml), IL-2 plus MLT, IL-2 plus IL-12 or IL-2 plus MLT and IL-12. Mean medium concentrations of IL-10 were measured by Elisa. IL-2 alone significantly stimulated IL-10 secretion with respect to the control medium alone, while no difference was observed with MLT alone or IL-12. IL-2-induced stimulation of IL-10 secretion was not abrogated by a concomitant MLT incubation. On the contrary, IL-12 significantly diminished IL-10 release in response to IL-2, and this inhibitory effect was more pronounced when IL-2 was added in association with both IL-12 and MLT. This preliminary study would suggest that the two most important immunosuppressive events occurring during IL-2 therapy, which are mediated by macrophages and TH2-lymphocytes, may be abrogated by a concomitant administration of MLT and IL-12, respectively. Therefore, the association of IL-12 could further amplify IL-2 efficacy with respect to IL-2 alone or IL-2 plus MLT.

J Biol Regul Homeost Agents 1995 Apr-Jun;9(2):63-6

A randomized study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma.

Our previous experimental studies have shown that the best approach to increase the biological anti-tumor activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumor regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumors other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomized to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumor objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.

Br J Cancer 1994 Jan;69(1):196-9

Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone.

The prognosis of brain glioblastoma is still very poor and the median survival time is generally less than 6 months. At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone M.

Oncology 1996 Jan-Feb;53(1):43-6

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

It is known that neoplastic cachexia shows metabolic characteristics different from other common causes of malnutrition, and that it is mainly due to an abnormal secretion of TNF, whose levels are often high in patients with advanced neoplasia. Previous clinical studies have suggested that the pineal hormone melatonin (MLT), which plays an essential role in the neuroendocrine regulation of biological systems, may improve the clinical status of advanced cancer patients and inhibit TNF secretion. To investigate the relationship between MLT, TNF and cancer-related weight loss, 100 untreatable metastatic solid tumor patients entered this study to receive either supportive care alone, or supportive care plus MLT (20 mg/day orally in the evening). Patients were observed for 3 months, and were considered evaluable when they were observed for at least 2 months. There were 86 evaluable patients, the other 14 patients having died from rapid progression of disease. The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01). Mean serum levels of TNF progressively increased in the supportive care group, but to levels that were not significantly different from pretreatment values. In contrast, TNF mean concentrations significantly decreased (P < 0.05) in patients concomitantly treated by MLT. These results suggest that the pineal hormone MLT may be effective in the treatment of the neoplastic cachexia by decreasing TNF blood concentrations.

Eur J Cancer 1996 Jul;32A(8):1340-3

The immunoneuroendocrine role of melatonin.

A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MIIO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as gamma-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.

J Pineal Res 1993 Jan;14(1):1-10

Sleep-inducing effects of low doses of melatonin ingested in the evening.

We previously observed that low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8 or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced “hangover” effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

Clin Pharmacol Ther 1995 May;57(5):552-8

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