Melatonin in Cancer Patients and in Tumor-Bearing Animals
A review of findings is given which relate to the levels of circulating melatonin as well as the urinary excretion of its main peripheral metabolite 6-sulphatoxymelatonin (aMT6s) in patients with different types of cancer as well as in tumor-bearing animals.
Clinical results show that circulating melatonin tends to be depressed in patients with primary tumors of different histological types including both endocrine-dependent (mammary, endometrial, prostate cancer) and endocrine-independent tumors (lung, gastric, colorectal cancer). Reduction of melatonin is most pronounced in patients with advanced localized primary tumors, such as mammary and prostate cancer where a clear negative correlation with tumor-size exists. The phenomenon of a reduction of circulating melatonin appears to be a transient one since patients with recidives show a normalization of melatonin. Surgical removal of the primary tumor does, however, not lead to normalization indicating that complex systemic changes appear to be involved in the down-regulation of melatonin. It is unclear at present, whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to certain peripheral metabolic processes, although no evidence for an enhanced hepatic degradation to aMT6s, the main peripheral metabolite of melatonin, was found. The reduction of circulating melatonin is accompanied by neuroendocrine changes affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone. In contrast to the above-described types of tumors many patients with ovarian cancer show highly elevated levels of melatonin perhaps due to the production of tissue-specific growth factors that could affect pineal melatonin secretion.
Experiments with tumor-bearing animals clearly demonstrate that nocturnal circulating melatonin is modulated due to malignant growth. Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocar-cinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth. As opposed to that nocturnal melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The reduction of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indoleamine 2,3-dioxygenase expressed in tumor and/or other tissues.
The significance of these clinical and experimental findings relating to melatonin is discussed both in terms of their practical application as a possible tumor marker and from a theoretical point of view to understand better the mechanisms involved in complex hosttumor interactions involving the neuroimmunoendocrine network.
KeywordsBenign Prostatic Hyperplasia Pineal Gland Plasma Melatonin Serial Transplant Primary Breast Cancer Patient
Unable to display preview. Download preview PDF.
- Anisimov, V.N., Kvetnoy, I.M., Chumakova, N.K., Kvetnaya, T.V., Molotkov, A.O., Pogudina, N.A., Popovich, I.G., Popuchiev, V.V., Zabezhinski, M.A., Bartsch, H., and Bartsch, C., 1999, Melatonin and colon carcinogenesis. II. Intestinal melatonin-containing cells and serum melatonin level in rats with 1,2-dimethylhydrazine-induced colon tumors, Exp. Toxic. Pathol. 51:47–52.CrossRefGoogle Scholar
- Bartsch, C., Bartsch, H., Flüchter, S.H., Harzmann, R., Bichler, K.-H., and Gupta, D., 1982, Serum melatonin and cortisol rhythms of patients with benign and malignant tumours of the prostate, Neuroendocrinol. Lett. 4:176. (Abstract).Google Scholar
- Bartsch, C., Bartsch, H., Flüchter, S.H., Harzmann, R., Attanasio, A., Bichler, K.-H., and Gupta, D., 1983, Circadian rhythms of serum melatonin, prolactin and growth hormone in patients with benign and malignant tumors of the prostate and in non-tumor controls, Neuroendocrinol. Lett. 5:377–386.Google Scholar
- Bartsch, C., Bartsch, H., Flüchter, S.-H., Attanasio, A., and Gupta, D., 1986, Melatonin rhythms in prostate cancer patients: effect of operation and hormone treatment, J. Neural Transm. Suppl. 21:491 (Abstract).Google Scholar
- Bartsch, C., 1988, Untersuchungen zur Funktion der Zirbeldrüse und ihrer Beziehung zum endokrinen System im Brust-und Prostatacarcinom: tierexperimentelle und humanbiologische Untersuchungen, ph.D. Thesis at the Faculty of Chemistry and Pharmacy, University of Tübingen, Tübingen.Google Scholar
- Bartsch, C., Bartsch, H., and Gupta, D., 1990, Pineal melatonin synthesis and secretion during induction and growth of mammary cancer in female rats, in: Neuroendocrinology: New Frontiers, (D. Gupta, H.A. Wollmann and M.B. Ranke, eds.), pp. 326–332, Brain Research Promotion, London, Tübingen.Google Scholar
- Bartsch, C., Bartsch, H., Schmidt, A., Ilg, S., Bichler, K.H., and Flüchter, S.H., 1992, Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations, Clin. Chim. Acta 209:153–167.PubMedCrossRefGoogle Scholar
- Bartsch, C. and Bartsch, H., 1994, Melatonin secretion in oncological patients: current results and methodological considerations, in: Advances in Pineal Research, Vol.7, (G.J.M. Maestroni, A. Conti and R.J. Reiter, eds.), pp. 283–301, John Libbey, London.Google Scholar
- Bartsch, C., Bartsch, H., Flüchter, S.H., Mecke, D., and Lippert, T.H., 1994, Diminished pineal function coincides with disturbed circadian endocrine rhythmicity in untreated primary cancer patients. Consequence of premature aging or of tumor growth? Ann. N. Y. Acad. Sci. 719:502–525.PubMedCrossRefGoogle Scholar
- Bartsch, C., Bartsch, H., Buchberger, A., Rokos, H., Mecke, D., and Lippert, T.H., 1995, Serial transplants of DMBA-induced mammary tumors in Fischer rats as model system for human breast cancer. IV Parallel changes of biopterin and melatonin indicate interactions between the pineal gland and cellular immunity in malignancy, Oncology 52:278–283.PubMedCrossRefGoogle Scholar
- Bartsch, C., Bartsch, H., Karenovics, A., Franz, H., Peiker, G., and Mecke, D., 1997a, Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size, J. Pineal Res. 23:53–58.PubMedCrossRefGoogle Scholar
- Bartsch, C., Kvetnoy, I., Kvetnaia, T., Bartsch, H., Molotkov, A., Franz, H., Raikhlin, N., and Mecke, D., 1997b, Nocturnal urinary 6-sulfatoxymelatonin and proliferating cell nuclear antigen-immunopositive tumor cells show strong positive correlations in patients with gastrointestinal and lung cancer, J. Pineal Res. 23:90–96.PubMedCrossRefGoogle Scholar
- Bartsch, C., Bartsch, H., Buchberger, A., Stieglitz, A., Effenberger-Klein, A., Kruse-Jarres, J.D., Besenthal, I., Rokos, H., and Mecke, D., 1999, Serial transplants of DMBA-induced mammary tumors in Fischer rats as a model system for human breast cancer. VI. The role of different forms of tumor-associated stress for the regulation of pineal melatonin secretion, Oncology 56(2):169–176.PubMedCrossRefGoogle Scholar
- Bartsch, C., Szadowska, A., Karasek, M., Bartsch, H., Geppert, M., and Mecke, D., 1999, Serial transplants of DMBA-induced mammary tumors in Fischer rats as model system for human breast cancer. V. Myoepithelial-mesenchymal conversion during passaging as possible cause for modulation of pineal-tumor interaction, Exp. Toxic. Pathol. (In Press).Google Scholar
- Bartsch, H., Bartsch, C., Mecke, D., and Lippert, T.H., 1993, The relationship between the pineal gland and cancer: seasonal aspects, in: Light and Biological Rhythms in Man, (L. Wetterberg, ed.), pp. 337–347, Pergamon Press, Oxford.Google Scholar
- Bartsch, H., Bartsch, C., Mecke, D., and Lippert, T.H., 1994a, Differential effect of melatonin on early and advanced passages of a DMBA-induced mammary carcinoma in the female rat, in: Advances in Pineal Research, Vol.7, (G.J.M. Maestroni, A. Conti and R.J. Reiter, eds.), pp. 247–252, John Libbey, London.Google Scholar
- Bergmann, W. and Engel, P., 1950, Über den Einflu von Zirbelextrakten auf Tumoren bei weien Mäusen und bei Menschen, Wien. Klin. Wochenschr. 62:79–82.Google Scholar
- Cardinali, D.P., 1984, Neural-hormonal integrative mechanisms in the pineal gland and superior cervical ganglia, in: The Pineal Gland, (R.J. Reiter, ed.), pp. 83–107, Raven Press, New York.Google Scholar
- Feigelson, P. and Greengard, O., 1962, Immunochemical evidence for increased titers of liver pyrrolase during substrate and hormonal enzyme induction, J. Biol. Chem. 237:3714–3717.Google Scholar
- Hofstätter, R., 1959, Versuche der postoperativen Krebsbehandlung mit Zirbelstoffen, Krebsarzt 14:307–316.Google Scholar
- Karasek, M., Marek, K., Zielinska, A., Swietoslawski, J., Bartsch, H., and Bartsch, C., 1994, Serial transplants of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Fischer rats as model system for human breast cancer. 3. Quantitative ultrastructural studies of the pinealocytes and plasma melatonin concentrations in rats bearing an advanced passage of the tumor, Biol Signals. 3:302–306.PubMedCrossRefGoogle Scholar
- Karasek, M., Dec, W., Kowalski, A.J., Bartsch, H., and Bartsch, C., 1996, Serum melatonin circadian profile in women with adenocarcinoma of uterine corpus, Int. J. Thymology 4 (Suppl.l):80–83.Google Scholar
- Klein, D.C., 1985, Photoneural regulation of the mammalian pineal gland, in: Photoperiodism, melatonin, and the pineal, Ciba Foundation Symposium 117, (D. Evered and S. Clark, eds.), pp. 38–51, Pitman, London.Google Scholar
- Schmidt, U.E., 1996, Untersuchungen zum Einfluß des Tumorwachstums auf die Melatoninsekretion der Rattenzirbeldrüse, ph. D.Thesis at the Faculty of Chemistry and Pharmacy, University of Tübingen, Tübingen.Google Scholar
- Touitou, Y., Fevre, M., Lagoguey, M., Carayon, A., Bogdan, A., Reinberg, A., Beck, H., Cesselin, F., and Touitou, C., 1981, Age-and mental health-related circadian rhythms of plasma levels of melatonin, prolactin, luteinizing hormone and follicle-stimulating hormone in man, J. Endocrinol. 91:467–475.PubMedCrossRefGoogle Scholar