Skip to main content
SpringerLink
Log in

Melatonin and Colon Carcinogenesis

  • Chapter
Book cover The Pineal Gland and Cancer

Abstract

It was shown earlier that melatonin (MLT) inhibits spontaneous and chemically induced mammary carcinogenesis and transplantable mammary tumor growth in vivo and in vitro. We have studied the effect of MLT on colon carcinogenesis. Three-month-old male LIO rats were exposed to 5 or 15 weekly s.c. injections of 1,2-di-methylhydrazine (DMH, 21 mg/kg). Part of the DMH-treated rats were given MLT in tap water (20 µg/ml) at nighttime during the period of carcinogen treatment. Rats were sacrificed 6 months after the first DMH injection. The exposure to MLT was followed by a decrease of intestinal tumor incidence in the jejunum and ascending colon as compared to controls. MLT inhibits the multiplicity and size of colon tumors as well as increasing tumor differentiation. The levels of immunohistochemically detected MLT in epithelium of the intestinal tract of rats exposed to DMH were significantly reduced as compared to intact rats, while in rats treated with DMH + MLT it was within the range of the controls. In the serum of rats exposed to DMH alone, the levels of diene conjugates (DC) and Schiff’s bases (SB) were significantly increased as compared with controls. In colon tissue of DMH-treated rats, the levels of DC, SB, and carbonyl derivatives of amino acid NO-synthase activity were significantly increased, while total antioxidative activity was decreased as compared to controls. In rats exposed to DMH + MLT, a normalization of free radical processes in serum and colon has been observed. MLT also inhibits the mutagenic effect of DMH in vivo (chromosome aberration and sperm head anomalies tests) and in vitro (Ames test). MLT also exerts some normalizing influence on glucose and lipid metabolism in rats exposed to DMH and inhibits proliferation and stimulates apoptosis in DMH-induced colon tumors. Thus, our data have shown that MLT affects initiating, promoting, and progression stages of colon carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Anisimov VN (1987) Carcinogenesis and Aging. Vols. 1 and 2. CRC Press, Boca Raton

    Google Scholar 

  • Anisimov VN (1998) In: Balducci L, Lyman GH, Ershler BW (eds) Comprehensive Geriatric Oncology. Harwood Acad Publ, Amsterdam, pp 157–178

    Google Scholar 

  • Anisimov VN, Reiter RJ (1990) Pineal function during cancer and ageing. Vopr Oncol 36: 259–268

    CAS  Google Scholar 

  • Anisimov VN, Azarova MA, Dmitrievskaya AY, Likhachev A, Petrov AS (1976) Disssemination of H3-dialkylhydrazines in the neuroendocrine system and their antigonadotropic effect in rats. Bull Exp Biol Med 82: 1473–1475

    CAS  Google Scholar 

  • Anisimov VN, Pozdeev VK, Dmitrievskaya AY, Gracheva GM, iPin AP (1976 a) Effect of the enterotropic carcinogen 1,2-dimethylhydrazine on the level of biogenic amines in the hypothalamus of rats. Bull Exp Biol Med 82: 1359–1361

    Google Scholar 

  • Anisimov VN, Pozharisski KM, Dilman VM (1980) Effect of phenformin on blastomogenic effect of 1,2-dimethylhydrazine. Vopr Onkol 26: 54–58

    PubMed  CAS  Google Scholar 

  • Anisimov VN, Khavinson VKh, Morozov VG (1994) Twenty years of study on effects of pineal peptide preparation: epithalamin in experimental gerontology and oncology. Ann NY Acad Sci 719: 483–493

    Article  PubMed  CAS  Google Scholar 

  • Anisimov VN, Khavinson VKh, Prokopenko VM (1995) Melatonin and epithalamin inhibit free radical oxidation in rats. Proc Russian Acad Sci 343: 557–559

    CAS  Google Scholar 

  • Anisimov VN, Arutyunian AV, Khavinson VKh (1996) Melatonin and epithalamin inhibit the process of lipid peroxidation in rats. Proc Russian Acad Sci 348: 265–267

    CAS  Google Scholar 

  • Anisimov VN, Zabezhinski MA, Popovich IG et al. (1996 a) Pineal hormone melatonin inhibits 1,2-dimethylhydrazine-induced colon carcinogenesis in rats: the role of free radical mechanisms. Int J Oncol 9 (Suppl): 834

    Google Scholar 

  • Anisimov VN, Arutyunian AV, Khavinson VKh (1997) Effect of melatonin and epithalamin on the activity of the antioxidant defense system in rats. Proc Russian Acad Sci 352: 831–833

    CAS  Google Scholar 

  • Anisimov VN, Popovich IG, Zabezhinski MA(1997a) Melatonin and colon carcinogenesis: I. Inhibitory effects of melatonin on development of intestinal tumors induced by 1,2-imethylhydrazine in rats. Carcinogenesis 18: 1549–1553

    Google Scholar 

  • Anisimov VN, Kvetnoy IM, Chumakova NK, Kvetnaia TV, Molotkov AO, Pogudina NA, Popovich VV, Popuchiev VV, Zabezhinski MA, Bartsch H, 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 Toxicol Pathol 51: 47–52

    PubMed  CAS  Google Scholar 

  • Anisimov VN, Popovich IG, Shtylik AV, Zabezhinski MA, Ben-Huh H, Gurevich P, Berman V, Tendler Y, Zusman I (2000) Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats. Exp Toxicol Pathol 52: 71–76

    PubMed  CAS  Google Scholar 

  • Arutyunyan AV, Prokopenko VM, Burmistrov SO, Opatina TI, Frolova EV, Zabezhinskii MA, Popovich IG, Anisimov VN (1997) Free radical processes in serum, liver and colon during carcinogenesis induced by 1,2-dimethylhydrazine in rats. Vopr Onkol 43: 618–622

    Google Scholar 

  • Awara WM, El-Gohary M, El-Nabi SH, Fadel WA (1998) In vivo and in vitro evaluation of the muta¬genic potential of carbamazepine: does melatonin have anti-mutagenic activity? Toxicology 125: 45–52

    Article  PubMed  CAS  Google Scholar 

  • Balanski R, Blagoeva P, Mircheva Z, Pozharisski K, de Flora S (1992) Effect of metabolic inhibitors, methylxanthines, antioxidants, alkali metals, and corn oil on 1,2-dimethylhydrzine carcinogenicity in rats. Anticancer Res 12: 933–940

    Google Scholar 

  • Bandaletova TY (1990) Concerning primary development of 1,2-dimethyl-hydrazine-induced cancer in lymphoid patches of the large bowel. Vopr Onkol 36: 1456–1460

    PubMed  Google Scholar 

  • Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD, Poeggeler B (1995) Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26: 497–502

    Article  PubMed  CAS  Google Scholar 

  • Barni S, Lissoni P, Cazzaniga M, Ardizzoia A, Mergalli S, Fossati V, Fumagalli L, Brivio F, Tancini G (1995) A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colon cancer patients progressing under 5-fluorouracil and folates. Oncology 52: 243–245

    Article  PubMed  CAS  Google Scholar 

  • Bartsch C, Bartsch H, Lippert TH (1992) The pineal gland and cancer: facts, hypotheses and perspectives. The Cancer J 5: 194–199

    CAS  Google Scholar 

  • Bartsch C, Kvetnoy I, Kvetnaya T, Bartsch H, Molotkov A, Franz H, Raikhlin N, Mecke D (1997) Noc¬turnal 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

    Article  PubMed  CAS  Google Scholar 

  • Bedi A, Pasricha PJ, Akhtar AJ, Barber JP, Bedi GC, Giardiello FM, Zehnbauer BA, Hamilton SR, Jones RJ (1995) Inhibition of apoptosis during development of colorectal cancer. Cancer Res 55: 1811–1816

    PubMed  CAS  Google Scholar 

  • Berstein LM (1995) The endocrinology of large bowel cancer. Endocrine-Related Cancer 2: 171–185

    Article  CAS  Google Scholar 

  • Blask DE (1993) Melatonin in oncology. In: Yu HS and Reiter RJ (eds) Melatonin Biosynthesis, Physiological Effects, and Clinical Applications. CRC Press, Boca Raton, pp 447–475

    Google Scholar 

  • Bubenik GA (1999) Localization and physiological significance of gastrointestial melatonin. In: Watson RR (ed) Melatonin in Health Promotion. CRC Books, Boca Raton, pp 21–39

    Google Scholar 

  • Cagnoli CM, Atabay C, Kharlamova E, Manev H (1995) Melatonin protects neurons from singlet oxygen-induced apoptosis. J Pineal Res 18: 222–226

    Article  PubMed  CAS  Google Scholar 

  • Callaghan BD (1995) The long-term effect of pinealectomy on the crypts of the rat gastrointestinal tract. J Pineal Res 18: 191–196

    Article  PubMed  CAS  Google Scholar 

  • Coleman MP, Esteve J, Damiecki P, Arslan A, Renard H (1993) Trends in Cancer Incidence and Mortality. IARC Sci Publ 121: 1–806

    PubMed  Google Scholar 

  • Dilman VM, Anisimov VN (1979) Hypothalamic mechanisms of ageing and of specific age patho-logy - I. Sensitivity threshold of hypothalamo-pituitary complex to homeostatic stimuli in the reproductive system. Exp Gerontol 14: 161–174

    Article  PubMed  CAS  Google Scholar 

  • Dilman VM, Sofronov BN, Anisimov VN et al. (1977) Withdrawal of 1,2-dimethylhydrazine-induc-ed immunodepression by phenformin in rats. Vopr Onkol 23: 50–54

    CAS  Google Scholar 

  • Hirose Y, Yoshimi N, Suzui M, Kawabata K, Tanaka T, Mori H (1997) Expression of bcl-2, bax, and bcl-XL proteins in azoxymethane -induced rat colonic adenocarcinomas. Mol Carcinogenesis 19: 25–30

    Article  CAS  Google Scholar 

  • Koratkar R, Vasudha A, Ramesh G et al. (1992) Effect of melatonin on cis-platinum induced genetic damage to the bone marrow cells of mice. Med Sei Res 20: 179–180

    CAS  Google Scholar 

  • Kothari L, Subramanian A (1992) A possible modulatory influence of melatonin on representative phase I and II drug metabolizing enzymes in 9,10-dimethyl-l,2-benzanthracene induced rat mammary tumorigenesis. Anti-Cancer Drugs 3: 623–628

    Article  PubMed  CAS  Google Scholar 

  • Kovalenko RI, Novikova I A, SibarovDA et al. (1998) Adaptive morphofunctional changes of pineal cells during tumor process in large intestine. Pathophysiology 5 (Suppl 1): 17

    Google Scholar 

  • Kvetnoy IM, Levin IM (1987) Diurnal melatonin excretion in stomach and colon cancer patients. Vopr Onkol 33: 29–32

    Google Scholar 

  • Kvetnoy I, Sandvik AK, Waldum HL (1997) The diffuse neuroendocrine system and extrapineal melatonin. J Mol Endoer 18: 1–3

    Article  CAS  Google Scholar 

  • Lewczuk B, Przybylska-Gornowicz B (1997) Effects of sympathicolytic and sympathicomimetic drugs on pineal ultrastructure in the domestic pig. J Pineal Res 23: 198–208

    Article  PubMed  CAS  Google Scholar 

  • Lewinski A, Rybicka I, Wajs E, Szkudlinski M, Pawlikowski M (1991) Influence of pineal indola- mines on the mitotic activity of gastric and colonic mucosa epithelial cells in the rat: interaction with omeprazole. J Pineal Res 10: 104–108

    Article  PubMed  CAS  Google Scholar 

  • Maskens AP (1987) Multistep carcinogenesis in the colorectal mucosa. In: Maskens AP, Ebbesen P, Burny A (eds) Concepts and Theories in Carcinogenesis. Excerpta Medica, Amsterdam, pp 221–242

    Google Scholar 

  • Musatov SA, Anisimov VN, Andre V, Vigreux C, Godard T, Gauduchon P, Sichel F (1998) Modulatory effects of melatonin on genotoxic response of reference mutagens in the Ames test and the COMET assay. Mutat Res 417: 75–84

    PubMed  CAS  Google Scholar 

  • Musatov SA, Rosenfeld SV, Togo EF, Mikheev VS, Anisimov VN (1997) The influence of melatonin on mutagenicity and antitumor action of cytostatic drugs in mice. Vopr Onkol 43: 623–627

    PubMed  CAS  Google Scholar 

  • Neri B, De Leonardis V, Gemelli MT, di Loro F, Mottola A, Ponchietti R, Raugei A, Cini G (1998) Melatonin as biological response modifier in cancer patients. Anticancer Res 18: 1329–1332

    PubMed  CAS  Google Scholar 

  • Okulov VB, Pozharisski KM (1975) Carcinoembryonic antigen in experimental intestinal tumours. Bull Exp Biol Med 80: 78–81

    Article  CAS  Google Scholar 

  • Panzer A, Viljoen M (1997) The validity of melatonin as an oncostatic agent. J Pineal Res 22: 184–202

    Article  PubMed  CAS  Google Scholar 

  • Pentney P (1995) An investigation of melatonin in the gastrointestinal tract. PhD Thesis, University of Guelph, pp 1–161

    Google Scholar 

  • Petrelli C, Moretti P, Petrelli F, Bramucci M (1992) A low molecular weight calf pineal peptide with an inhibiting effect on the growth of L1210 and HL60 cells. Cell Biol Int Rep 16: 967–974

    Article  PubMed  CAS  Google Scholar 

  • Pierrefiche G, Topall G, Courboin G, Henriet I, Laborit H (1993) Antioxidant activity of melatonin in mice. Res Commun Chem Pathol Pharmacol 80: 211–223

    PubMed  CAS  Google Scholar 

  • Pozharisski KM, Anisimov VN (1975) On the role of endocrine system in development of experi¬mental colon tumors in rats. Pathol Physiol 1: 47–50

    Google Scholar 

  • Pozharisski KM, Likhachev AJ, Klimashevski VF, Shaposhnikov JD (1979) Experimental intestinal cancer research with special reference to human pathology. Adv Cancer Res 30: 165–237

    Article  PubMed  CAS  Google Scholar 

  • Reiter RJ, Carneiro RC, Oh C-S (1997) Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res 29: 363–372

    Article  PubMed  CAS  Google Scholar 

  • Reyes-Vazquez C, Prieto-Gomez B, Aides LD, Dafny N (1986) Rat pineal exhibits two electro¬physiological patterns of response to microiontophoretic norepinephrine application. J Pineal Res 3: 213–222

    Article  PubMed  CAS  Google Scholar 

  • Roos JS (1992) Experimental large intestinal adenocarcinoma induced by hydrazine and human colorectal cancer: a comparative study. In: Malt RA, Williamson RCN (eds) Colon Carcinogenesis. Proc. of 31st Falk Symp, Titisee Lancaster, pp 187–210

    Google Scholar 

  • Salim AS (1993) The permissive role of oxygen-derived free radicals in the development ot colonic cancer in the rat. A new theory for carcinogenesis. Int J Cancer 53: 1031–1035

    Article  PubMed  CAS  Google Scholar 

  • Samaha HS, Kelloff GJ, Steele V, Rao CV, Reddy BS (1997) Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion. Cancer Res 57: 1301–1305

    PubMed  CAS  Google Scholar 

  • Semm P, Schneider T, Vollrath L (1981) Morphological and electrophysiological evidence for habenular influence on the guinea-pig pineal gland. J Neural Transm 50: 247–266

    Article  PubMed  CAS  Google Scholar 

  • Shimamoto F, Vollmer E (1987) Changes in intestinal mucosa above lymph follicles during carcinogenesis in rats. A light and electron microscopic study. J Cancer Res Clin Oncol 113: 41–50

    Article  PubMed  CAS  Google Scholar 

  • Steele G, Sjogren HO (1974) Cross-reacting tumor-associated antigen(s) among chemically induced rat colon carcinomas. Cancer Res 34: 1801–1807

    PubMed  CAS  Google Scholar 

  • Susa N, Ueno S, Furukawa Y, Ueda J, Sugiyama M (1997) Potent protective effect of melatonin on chromium(VI)-induced DNA single-strand breaks, cytotoxicity, and lipid peroxidation in primary cultures of rat hepatocytes. Toxicol Appl Pharmacol 144: 377–384

    Article  PubMed  CAS  Google Scholar 

  • Tan D, Reiter RJ, Chen L, Poeggeler B, Manchester LC, Barlow-Waiden LR (1994) Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. Carcinogenesis 15: 215–218

    Article  PubMed  CAS  Google Scholar 

  • Tendier Y, Ben-Hur H, Gurevich P, Berman V, Sandler B, Nyska A, Zion H, Zinder O, Zusman I (1997) Role of apoptosis, proliferating cell nuclear antigen and p53 protein in the immune response of the rat colon cells to cancer and vaccination with the anti-p53 polyclonal antibodies. Anticancer Res 17: 4653–4658

    Google Scholar 

  • Ubeda A, Trillo MA, House DE, Blackman CF (1995) Melatonin enhances junctional transfer in normal C3H/10T1/2 cells. Cancer Lett 91: 241–245

    Article  PubMed  CAS  Google Scholar 

  • Vijayalaxmi, Reiter RJ, Leal BZ, Meltz ML (1996) Effect of melatonin on mitotic and proliferation indices, and sister chromatid exchange in human blood lymphocytes. Mutat Res 351: 187–192

    Article  PubMed  Google Scholar 

  • Windle R, Bell PRF (1982) Lipid clearance in a colonic tumour model in rats. Br J Cancer 46: 515

    Google Scholar 

  • Yu HS, Reiter RJ (eds) (1993) Melatonin Biosynthesis, Physiological Effects, and Clinical Applications. CRC Press, Boca Raton

    Google Scholar 

  • Zusman I (1997) The role of p53 tumor-associated protein in colon cancer detection and preven¬tion (review). Int J Oncol 10: 1241–1249

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Vladimir N. Anisimov
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Centre for Research in Medical and Natural Sciences, University of Tübingen, Ob dem Himmelreich 7, Tübingen, 72074, Germany

    Christian Bartsch  & Hella Bartsch  & 

  2. Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, One Atwell Road, Cooperstown, NY, 13326, USA

    David E. Blask Ph.D.,M.D. (Senior Research Scientist) (Senior Research Scientist)

  3. Department of Physiology Faculty of Medicine, University of Buenos Aires, Paraguay 2155, Buenos Aires, 121, Argentina

    Daniel P. Cardinali M.D.,Ph.D.

  4. WJB Dorn VA Medical Center, University of South Carolina, 6439 Garners Ferry Road, Columbia, SC, 29209, USA

    William J. M. Hrushesky M.D. (Director of Research (151) (Director of Research (151)

  5. Institute of Physiological Chemistry, University of Tübingen, Hoppe-Seyler-Str. 4, Tübingen, 72076, Germany

    Dieter Mecke (Director) (Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Anisimov, V.N. (2001). Melatonin and Colon Carcinogenesis. In: Bartsch, C., Bartsch, H., Blask, D.E., Cardinali, D.P., Hrushesky, W.J.M., Mecke, D. (eds) The Pineal Gland and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59512-7_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59512-7_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64003-2

  • Online ISBN: 978-3-642-59512-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation