NEOPLASMA, 49,4,2002  255 Nimesulide and melatonin in mammary carcinogenesis prevention in female  Sprague-Dawley rats  Р. КивАТКА, K. KALICKÁ, M. CHAMILOVÁ, E. AHLERSOVÁ , I. AHLERS, B. BOJKOVÁ, E. ADÁMEKOVÁ Institute of Animal Physiology, Faculty of Science, P.J. Šafárik University, 041 67 Košice, Slovak Republic, e-mail: iahlers@kosice.upjs.sk Received February 14, 2002 Tumorsuppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2) nimesulide (NIM) activity and pineal hormone melatonin (MEL) and their combination in two chemopreventive studies of mammary carcinogenesis were evaluated. Mammary tumors in female Sprague-Dawley rats were induced by N-methyl-N-nitrosourea (NMU) and by 7,12-dimethylbenz(a)anthraccne (DMB A), respectively. The treatment with NIM (applied subcutaneously twice a week in the dose of 5 mg/kg b. w.) and MEL (given daily diluted in drinking water in concentration 20 /<g/ml) began several days before carcinogen administration and lasted until the end of the experiment. The tumor incidence, frequency, latency period and tumor volume as parameters of mammary carcinogenesis were evaluated. Moreover, the effect of chemopre- ventives on body weight, food and water intake were recorded. Changes of selected parameters of lipid and carbohydrate metabolism in the serum and chosen organs were evaluated in the NMU experiment. In the NIM-treated group in the NMU experiment, the tumor incidence decreased by 34.5% (p < 0.05), tumor frequency per group by 40% (p < 0.05) and tumor volume gain by 39% when compared to the control group. Tumorsuppressive effect of MEL was not observed. In DMB A-induced carcinogenesis an oncostatic effect of NIM was not observed; MEL admin- istration decreased tumor incidence by 21.5% (p<0.05), tumor frequency per group by 22.5% and tumor volume gain by 43.5%. Combined chemoprevention of NIM+MEL was very similar to that of chemopreventives administered alone. MEL lowered food and water intake and body weight gain in DMBA-induced carcinogenesis. It increased glycogen and cho- lesterol content in the liver, triacyglycerol and phospholipid concentrations in the bone marrow and decreased malondial- dehyde concentration at the same tissue of tumor-bearing animals. NIM did not significantly influence the selected metabolic parameters, excepting the decrease in serum glucose concentration in tumor-bearing rats. Key words: Chemoprevention, rat, mammary carcinogenesis, nimesulide, melatonin, metabolism. The non-steroidal anti-inflammatory drugs (NSAIDs) suppress manifestations of inflammation (pain, edema, etc.). Their mechanism is based on suppression of prosta- noid synthesis (originating from arachidonic acid cascade) by inhibition of cyclooxygenase activity (COX). Two iso- forms of COX were identified: constitutive COX-1 present in all cells/tissues; inducible COX-2 isoform found mostly under pathological conditions (e.g. inflammation or neopla- sias, respectively) stimulated by some cytokines, growth factors, factors promoting tumor growth, bacterial lipopoli- "The project 1/7397/20 was supported by VEGA, SR. The experiments were conducted according to the principles provided in the Law No. 115/1995 §24 of the Slovak Republic for the Care and Use of Laboratory Animals. "Author to whom correspondence should be sent. saccharides [2]. An increased activity of COX-2 isoform was found in colorectal, esophagus, stomach and breast carcino- mas [17,8,28]. Clinical trials aimed at long-term application of oldest NSAIDs - aspirin (prevailing inhibitor of COX-1) in prevention of myocardial ischemia simultaneously re- ported decreased incidence of colon tumors [29]. Similar results were observed in women with breast carcinoma in central Ohio: regular administration of Ibuprofen decreased mammary tumor incidence by 50% and that of aspirin by 40% [9]. Studies with laboratory animals proved chemopre- ventive effects of NSAIDs in various types of neoplasia including in mammary gland [20, 27]. The oncostatic prop- erties of NSAIDs consist of inhibition of malondialdehyde DNA adducts and carcinogenic epoxides formation [8], in- hibition of immunosuppressive effect of some prostaglan-