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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): 73-78 PubMed PMID: 12019356 Citation  Keywords:  Animals, Antioxidants:metabolism, Humans, Melatonin:physiology, Pineal Gland:drug effects, Thyroid Gland:growth & development, Thyroid Hormones:pharmacology,.   

: This review briefly summarizes the published data on relationships observed between melatonin - the main pineal hormone, and the thyroid gland. The prevailing part of the survey is devoted to thyroid growth processes and function. A large experimental evidence exists suggesting the inhibitory action of melatonin on thyroid growth and function; this effect has been revealed by using different experimental models: by chronic and short-term melatonin administration in vivo, by light restriction, which is known to increase the activity of the pineal gland, by pinealectomy, etc., as well as by employing the in vitro conditions. Thus, much information has been accumulated, indicating - in experimental conditions - a mutual relationship between the pineal gland and the thyroid. The confirmation of these relations in clinical studies in humans meets numerous difficulties, resulting - among others - from the fact that, nowadays, human beings, as well as certain animal species, used in experimental studies, have been living far away from their natural and original habitat. It makes almost impossible to compare the results obtained in particular studies performed in different species, on the pineal-thyroid interrelationship....

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Journal Article 2002; 23(Suppl 1): 67-72 PubMed PMID: 12019355 Citation  Keywords:  Animals, Antioxidants:pharmacology, Cell Division:drug effects, Cell Membrane:drug effects, Cells, Cultured, Chickens:physiology, Colforsin:pharmacology, Cyclic AMP:metabolism, Lymphocytes:drug effects, Male, Melatonin:pharmacology, Phytohemagglutinins:ph.   

OBJECTIVES: Time-dependent melatonin effects on chicken lymphocyte proliferation in vitro and the involvement of cAMP in melatonin signal transduction were examined.

MATERIALS AND METHODS: Splenocytes and peripheral blood mononuclear cells (PBMC) were cultured in vitro in the presence of melatonin, phytohemagglutinin, luzindole, dibutyrylcAMP (dbcAMP), forskolin and vasoactive intestine peptide (VIP). Proliferation was measured by [(3)H]-thymidine incorporation in cultures carried out for 24, 36, 48 and 72 h. Cyclic AMP formation was assessed by radioimmunoassay in cells incubated for 30 min. or 24 h.

RESULTS: Melatonin stimulated the spontaneous proliferation in short-term (36 and 48 h) splenocyte cultures and had no effect in 72 h cultures. It inhibited mitogen-stimulated proliferation already in 24 h cultures and this effect was observed regardless of the time of the culture. Both melatonin effects were antagonized by luzindole - membrane-bound melatonin receptor antagonist. Forskolin and dbcAMP caused a significant inhibition of proliferation of splenocytes and PBMC cultured for 24 or 72 h, respectively. Melatonin inhibited the cAMP formation (30 min. of incubation) stimulated by adenosine cyclase activators - forskolin and VIP, but added alone failed to affect the cAMP concentration. In mitogen-stimulated splenocytes cultured for 24 h Mel caused an increase in cAMP correlated with the inhibition of cell proliferation.

CONCLUSIONS: Melatonin effects on chicken splenocytes appears time- and activation-dependent: in short-term cultures it stimulates spontaneous and inhibits mitogen-activated proliferation, probably via membrane-bound, luzindole-sensitive melatonin receptors. Incubation with melatonin for 30 min. inhibits cAMP formation, but in 24 h cultures it increases cAMP concentration leading to inhibition of proliferation....

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Comparative Study 2002; 23(Suppl 1): 61-66 PubMed PMID: 12019354 Citation  Keywords:  Animals, Antioxidants:pharmacology, Humans, Immunity:drug effects, Melatonin:pharmacology, Pineal Gland:physiology, Receptors, Cell Surface:physiology, Receptors, Cytoplasmic and Nuclear:physiology, Receptors, Melatonin, Seasons,.   

: Pineal gland, by the diurnal rhythm of synthesis and release of its principal hormone, melatonin (MEL), is involved in reciprocal relationships between neuroendocrine and immune systems, responsible for keeping internal homeostasis in vertebrate animals. In this paper the experimental data, indicating that both strategic (developmental, thus antigen independent) and emergency (evoked by antigenic activation of the mature immune system) levels of interactions between pineal gland and immune system, operate in mammals and birds, are reviewed. The cells and organs of immune system using membrane receptors as well as nuclear orphan receptors perceive MEL message. Effects exerted by MEL on immune parameters are different, and depend on several factors, including dose and way of MEL application, species, sex, age of animal, its immune system maturation, way of immune system activation, and parameter examined, as well as the season, circadian rhythm of both immunity and pineal gland function, stressful conditions, accompanying experimental procedure, etc. In turn, lymphoid organ-derived hormones and cytokines, soluble factors secreted by activated immune cells act as messages understood by the pineal gland, closing the regulatory loop of the bi-directional functional connections between both systems....

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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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