It is known that the pineal gland has some antitumor activity. Melatonin, its most important hormone, has been shown to inhibit tumor growth in vivo and in vitro. Moreover, some investigations have demonstrated an altered melatonin secretion in cancer patients. Despite these interesting data, clinical trials have never been carried out to evaluate the effects of melatonin on human neoplasms. The aim of this study was to draw some preliminary conclusions on melatonin therapy in advanced human neoplasms. Nineteen patients suffering from advanced solid tumors, which did not respond to standard therapies, entered the study. Performance status (PS) was 20 or less in 9 cases, and more than 20 in the other 10. Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period with lower doses in patients who had a remission, a stabilization of disease or an improvement in PS. Among patients with a PS higher than 20, a partial response was achieved in one case with cancer of the pancreas; moreover, 5 of 10 had stable disease, but the other 4 cases had a progression; an evident improvement of PS was obtained in 6 of the 10 cases. In contrast, among patients with a very poor PS, 7 of 9 died within the first 2 months of therapy. This preliminary study would suggest that melatonin may be of some value in treating cancer patients in whom standard antitumor therapies have failed, particularly in improving their PS and quality of life.

The pineal hormone melatonin (MLT) is able to exert an oncostatic action. Its possible use in the treatment of human tumors, however, has not yet been investigated. The present study was carried out to evaluate the effects of MLT in patients with metastatic solid tumors resistant to conventional therapies. The study included 54 patients, most of them were affected by lung cancer or colorectal carcinoma. MLT was given intramuscularly at a daily dose of 20 mg at 3.00 p.m. for 2 months; this induction phase was followed by a maintenance period at a dose of 10 mg orally in responder patients or in those with an improvement in performance status (PS). The clinical response was as follows: 1 partial response (cancer of pancreas), 2 minor responses (colon cancer and hepatocarcinoma) and 21 with stable disease. The remaining 30 patients rapidly progressed within the first 2 months of therapy. An evident improvement in PS was achieved in 18 of 54 (33%) cases. These results, by showing an apparent control of the neoplastic growth and an improvement in the quality of life in a reasonable number of cancer patients for whom no other standard therapy is available, would justify further clinical trials to better define the impact of MLT therapy on the survival and quality of life of untreatable advanced cancer patients.

It is well known that the pineal gland can modulate the secretion of pituitary hormones. Melatonin, the main hormone produced by the pineal gland, acts at the hypothalamic site, whereas hypophyseal sensitivity to melatonin seems to change with age. To investigate the influence of pubertal development on the role of the pineal gland in the regulation of the secretion of pituitary hormones, FSH, LH, Prl, TSH and GH responses to melatonin were evaluated in a group of 9 prepubertal and 10 pubertal healthy subjects of both sexes. Melatonin was given im at a dose of 0.2 mg/kg body weight at 3 p.m. Venous blood samples were drawn \m=-\20,0, 20, 40, 60, 90, 120, 180 and 240 min, after melatonin injection. According to the same experimental protocol, venous blood samples were collected during a saline infusion on a separate occasion. FSH, LH, Prl, TSH and GH plasma levels were measured with RIA. In pubertal subjects, a significant rise in the mean Prl levels was seen 90 min after melatonin as compared with those during saline infusion. The Prl melatonin response area was significantly lower in prepubertal treated subjects and significantly higher in pubertal ones compared with the respective controls. The mean GH values showed a significant decrease 120 min after melatonin only in prepubertal subjects; no significant variations were seen in 8 of 10 pubertal subjects, whereas in the last 2 a marked increase was observed. Finally, under these conditions, melatonin did not influence the basal FSH LH and TSH levels.These results seem to suggest that hypophyseal hormone reponses change with pubertal development.

Recent reports point to a link between the pineal gland and the opioid system. In order to investigate this relationship, two separate studies were performed on humans. Beta-endorphin plasma levels were determined after melatonin administration (0.2 mg/kg b.w. i.m. at 2 p.m.). Melatonin serum values were evaluated after administration of FK 33-824, a met-enkephalin analogue (0.3 mg i.v. infusion at 9 a.m.). A significant decrease of beta-endorphin plasma levels was observed 120 minutes after melatonin injection. Melatonin release was stimulated by FK 33-824, with a peak at 30 minutes. The present results provide evidence of the inhibitory effect of melatonin on beta-endorphin secretion and the stimulatory action of the opioid peptides on the pineal gland. However, further studies will be required to clarify the relationship between the opioid system and the pineal gland.

The mechanisms by which tetrahydrocannabiol (A'-THC) affects some neuroendocrine activities have not yet been clarified. Its effects cannot be prevented by pretreatment with a-methyltyrosine, which reduces brain concentrations of norepinephrine and dopamine (Hollister 1971). At present, the existence of an endogenous agonist cannot be excluded. To investigate whether its effects involve the participation of the pineal gland, the response of melatonin (the main pineal hormone), to A'-THC was evaluated in nine agreeing healthy male volunteers, aged between 29 and 33. The substance was administered at 3 p.m. through a 1 g cigarette containing 1% A 9 -THC. Venous blood samples were drawn from an indwelling catheter in an antecubital vein -20, 0, 20, 60 and 120 mins. after drug administration. According to the same experimental protocol, on the preceding day the test had been performed after smoking one normal cigarette. The whole test was carried out in summer. Sera were separated by centrifugation and stored at -20° C until assayed. Melatonin serum values were measured by means of the RIA method described by Wetterberg, Erickson, Friberg and Vangbo (1978), using commercially available kits (WHBSweden) when the extracts showed melatonin values higher than detection limit, samples were measured after an adequate dilution. Data were analyzed by Student's t-test and results reported as the mean + SD. A very high significant increase (P < 0.001) of melatonin serum mean levels, in comparison to the values observed during saline infusion, was noticed in eight of the nine subjects after A'-THC administration; the highest values were obtained at 120 mins. from administration (Table 1).In contrast, the last case showed high basal levels of melatonin (289.3 -321.3 -157.0 -72.5 -181.2 pg/ml, respectively at -20, 0, 20, 60, 120 mins.) without evidence of endocrine or psychiatric disorders, and melatonin peak was significantly inhibited (P < 0.001) by A'-THC, with the lowest levels reached 60 mins. later (304.2 -311.7 -294.2 -306.0 -314.8 pg/ml respectively at-20, 0, 60, 120 mins.).These preliminary results are difficult to interpret moreover, at present we are unable to explain the hight melatonin basal level observed in the last case. However, the present data, suggest that A'-THC may regulate the activity of the pineal gland either by stimulating or inhibiting melatonin secretion, and that melatonin response to A'-THC seems to depend upon its basal levels. MoreDownloaded by: University of Illinois. Copyrighted material.