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Journal Article 2002; 23(Suppl 1): 92-96 PubMed PMID: 12019360 Citation  Keywords:  Diagnosis, Humans, Melatonin:blood, Neoplasms:blood, Pineal Gland:metabolism, Prognosis, Tissue Distribution,.   

: During the last decade, attention was concentrated on melatonin -- one of the hormones of the diffuse neuroendocrine system, which has been considered only as a hormone of the pineal gland, for many years. Currently, melatonin has been identified not only in the pineal gland, but also in extrapineal tissues -- retina, harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and endometrium as well as in non-neuroendocrine cells like mast cells, natural killer cells, eosinophilic leukocytes, platelets and endothelial cells. The above list of the cells storing melatonin indicates that melatonin has a unique position among the hormones of the diffuse neuroendocrine system, which is present in practically all organ systems. Functionally, melatonin-producing cells are certain to be part and parcel of the diffuse neuroendocrine system as a universal system of response, control and organism protection. Taking into account the large number of melatonin-producing cells in many organs, the wide spectrum of biological activities of melatonin and especially its main property as a universal regulator of biological rhythms, it should be possible to consider extrapineal melatonin as a key paracrine signal molecule for the local coordination of intercellular relationships. Analysis of our long-term clinical investigations shows the direct participation and active role of extrapineal melatonin in the pathogenesis of tumor growth and many other non-tumor pathologies such as gastric ulcer, immune diseases, neurodegenerative processes, radiation disorders, etc. The modification of antitumor and other specific therapy by the activation or inhibition of extrapineal melatonin activity could be useful for the improvement of the treatment of illness....

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Journal Article 2002; 23(Suppl 1): 84-87 PubMed PMID: 12019358 Citation  Keywords:  Animals, Anticarcinogenic Agents:pharmacology, Electromagnetic Fields:adverse effects, Humans, Melatonin:pharmacology, Neoplasms:epidemiology,.   

: There is public health concern raised by epidemiological studies indicating that extremely low frequency electric and magnetic fields generated by electric power distribution systems in the environment may be hazardous. Possible carcinogenic effects of magnetic field in combination with suggested oncostatic action of melatonin lead to the hypothesis that the primary effects of electric and magnetic fields exposure is a reduction of melatonin synthesis which, in turn, may promote cancer growth. In this review the data on the influence of magnetic fields on melatonin synthesis, both in the animals and humans, are briefly presented and discussed....

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Journal Article 2002; 23(Suppl 1): 55-60 PubMed PMID: 12019353 Citation  Keywords:  Animals, Blotting, Southern, Blotting, Western, Cell Membrane:metabolism, Cell Nucleus:metabolism, Colonic Neoplasms:genetics, Gene Expression Regulation, Neoplastic:genetics, Male, Mice, Neoplasm Transplantation, Nuclear Receptor Subfamily 1, Group F, Me.   

OBJECTIVES: There are some data suggesting that melatonin exerts oncostatic action through membrane as well as nuclear receptors. In previous studies we demonstrated the antiproliferative and proapoptotic action of melatonin on transplantable murine Colon 38 adenocarcinoma cells. Therefore, the aim of the present study was to determine whether the membrane melatonin receptors MT(1) and MT(2) as well as the nuclear receptor RZR/ROR alpha are expressed in Colon 38 cells.

MATERIAL AND METHODS: Adult male B6D2F1 mice were used in this experiment. The induction of tumor was conducted by subcutaneous injection of 0.2 mL of a 33% suspension of Colon 38 cancer cells into axillary region. Expression of mRNA encoding MT(1) and MT(2) melatonin membrane receptors was studied by RT-PCR analysis, and expression of ROR alpha(1) nuclear receptor protein was studied by Western blot analysis.

RESULTS: The expression of mRNA encoding both MT(1) and MT(2) melatonin receptors was demonstrated in Colon 38 cancer cells. Moreover, immunodetection revealed the expression of MT(1) and ROR alpha(1) proteins in these cells.

CONCLUSIONS: Our studies on Colon 38 adenocarcinoma cells support the concept that both membrane and nuclear receptors are involved in the oncostatic action of melatonin....

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Journal Article 2002; 23(Suppl 1): 50-54 PubMed PMID: 12019352 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacology, Antioxidants:pharmacology, Apoptosis:drug effects, Bromodeoxyuridine, Cell Division:drug effects, Colonic Neoplasms:drug therapy, Indoles:pharmacology, Ligands, Melatonin:antagonists & inhibitors, Mice, Mice, I.   

OBJECTIVES: Our previous study suggest that oncostatic action of melatonin (MLT) depends mainly on nuclear RZR/ROR receptors. However, we cannot exclude the involvement of membrane receptors in the control of tumor growth. In the present study the effects of MLT and N-[(4-methoxy-1H-indol-2-yl)methyl]propanamide (UCM 386 - antagonist of membrane MT(1) receptor and partial agonist of membrane MT(2) receptor) on murine transplantable Colon 38 cancer were investigated in vitro and in vivo conditions.

MATERIAL AND METHODS: The experiments were performed on adult male B6D2F1 mice strain. In vitro the cell proliferation was measured using modified Mosmann method. In the experiment performed in vivo, we assessed the cell proliferation, apoptosis and proliferation/apoptosis ratio (P/A). The incorporation of bromodeoxyuridine into tumor cell nuclei was used as an index of cell proliferation (labeling index-LI). The labeling of apoptotic cells according to TUNEL method was considered as an index of apoptosis (AI).

RESULTS: In vitro MLT and UCM 386 decreased the cell proliferation, but administration of MLT and UCM 386 together did not change the inhibitory effect of MLT alone. In vivo MLT and UCM 386 alone decreased LI and the addition of UCM 386 to MLT did not diminish the antiproliferative effect of MLT. Melatonin and UCM 386 injected alone also increased the AI. Moreover, both compounds given together exerted the additive effect on tumor apoptosis. MLT and UCM 386 alone or together also significantly decreased P/A ratio which is additional parameter confirming the inhibition of tumor growth.

CONCLUSION: The obtained data together with our earlier observations suggest that oncostatic effect of MLT depends on acting via both MT(2) and RZR/ROR nuclear receptors...

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Journal Article 2002; 23(Suppl 1): 45-49 PubMed PMID: 12019351 Citation  Keywords:  Antioxidants:pharmacology, Cell Cycle:drug effects, DNA:metabolism, Electrophoresis, Flow Cytometry, Humans, Male, Melatonin:pharmacology, Mutation:genetics, Prostatic Neoplasms:metabolism, Receptors, Androgen:drug effects, Response Elements:drug effects,.   

OBJECTIVES: The pineal hormone melatonin inhibits the growth of benign human prostate epithelial cells and the androgen-dependent prostate cancer LNCaP cells. In the androgen-nonresponsive prostate carcinoma PC3 cells melatonin inhibits cell growth only at high but not low cell density. We have recently found that melatonin causes nuclear exclusion of the AR and attenuates it transcriptional activity in LNCaP cells as well as PC3 cells stably transfected with a wild type AR expressing vector (PC3-AR). The aim of this study was to investigate whether melatonin inhibits effects of AR on cell growth in PC3-AR cells and whether inhibition of AR DNA binding is involved.

METHODS: The effects of androgen, melatonin and their combination on the growth of the PC3-AR cells and on AR DNA binding in PC3-AR and LNCaP cells were studied.

RESULTS: DHT suppressed cell growth in the PC3-AR cells and enhanced AR binding to the androgen responsive element (ARE). Melatonin had no effect on cell growth in the absence of DHT but counteracted the androgen-induced inhibition at low androgen concentrations. Melatonin did not suppress and even slightly enhanced the capacity of AR binding to the ARE in the PC3-AR as well as in LNCaP cells.

CONCLUSIONS: Attenuation by melatonin of AR activity in the prostate cancer cells is not due to suppression of AR binding to the ARE, and is presumably caused by its effects on AR protein interaction and intracellular trafficking....

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Journal Article 2002; 23(Suppl 1): 30-38 PubMed PMID: 12019349 Citation  Keywords:  Antineoplastic Agents:therapeutic use, Antioxidants:metabolism, Clinical Trials as Topic, Humans, Melatonin:metabolism, Neoplasms:drug therapy, Pineal Gland:physiology,.   

: The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status)....

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Journal Article 2002; 23(Suppl 1): 24-29 PubMed PMID: 12019348 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacology, Humans, Melatonin:pharmacology, Neoplasms:drug therapy, Neoplasms, Experimental:drug therapy,.   

: The paper presents the data concerning the in vivo effects of melatonin on experimentally-induced tumors in animals and the in vitro effects on animal and human tumor cells. The majority of experimental tumors responded to the melatonin treatment with growth inhibition. However, some negative or opposite results (i.e. stimulation of tumor instead of inhibition) were also reported. Some of the negative results can be attributed to the improper timing of melatonin administration. Melatonin was also shown to inhibit the growth of several animal and human tumor cell lines in vitro. On the basis of these experiments, a hypothesis of the oncostatic action of melatonin was put forward. The mechanism of the postulated action is complex and probably includes: 1) modulation of the endocrine system; 2) modulation of the immune system; 3) the direct oncostatic action of melatonin on tumor cells. The latter includes the recently discovered anti-oxidative action which probably plays an important role in the countering the DNA damage during the radiation challenge or the exposure to chemical carcinogens. It also includes the antiproliferative and pro-apoptotic effects exerted via melatonin receptors expressed by tumor cells. The involvement of the membrane melatonin receptors is mainly assumed. However, the recent data from our and other laboratories suggest also the involvement of RZR/ROR receptors (the putative melatonin nuclear receptors) in both melatonin-induced proliferation inhibition and apoptosis....

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Clinical Trial 2002; 23(1): 61-63 PubMed PMID: 11880864 Citation  Keywords:  Aged, Androgen Antagonists:therapeutic use, Anilides:therapeutic use, Humans, Levodopa, Male, Middle Aged, Nitriles, Prolactin:blood, Prostatic Neoplasms:blood, Tosyl Compounds,.   

OBJECTIVES: The secretion of prolactin (PRL), which is a growth factor for prostate cancer cell proliferation, has been proven to present profound alterations in advanced prostate cancer patients, consisting of abnormally elevated baseline levels and paradoxical response to L-dopa. Moreover, the efficacy of standard therapies for prostate cancer may be mediated at least in part by changes in PRL secretion. The present study was carried out to analyze the effects of the new antiandrogen agent bicalutamide on basal levels of PRL and on its response to L-dopa in metastatic prostate cancer patients.

MATERIAL & METHODS: The study included 10 metastatic prostate cancer patients. They were treated with bicalutamide at a dose of 50 mg/day orally. They were investigated with L-dopa test before therapy and after one month of treatment. L-dopa was given orally at 500 mg, by collecting blood samples before and at 60, 120 and 180 minutes after L-dopa administration. Serum levels of PRL were measured by the RIA method.

RESULTS: Abnormally basal levels of PRL were seen in 4/10 (40%) patients. Mean PRL basal levels decreased after bicalutamide therapy, without, however, significant differences. Before therapy, a paradoxical increase in PRL levels after L-dopa occurred in 4 patients, 3 of them showed basal concentrations of PRL within the normal range. Moreover, bicalutamide therapy significantly reduced PRL increase in response to L-dopa.

CONCLUSIONS: This study would suggest that the measurement of the only basal levels is not sufficient to define as normal the secretion of PRL in advanced prostate cancer, because of the possible existence of altered response to the dynamic tests for PRL secretion. Moreover, the study shows that the antitumor therapy with the new anti-androgen bicalutamide may reduce PRL secretion and improve its paradoxical secretion in response to L.-Dopa. Further studies will be required to better define the possible prognostic impact of changes in PRL secretion on the efficacy of treatments for metastatic prostate cancer....

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