Rosiglitazone shows partial oncostatic effect in rat mammary carcinogenesis.

Peroral antidiabetics from thiazolidinedione (glitazone) group showed oncostatic effects in preclinical models. This study evaluated chemopreventive effects of rosiglitazone in N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. N-methyl-N-nitrosourea was administered in two intraperitoneal doses each per 50 mg/kg b.w. between 40th and 51st postnatal days. Rosiglitazone was administered in a diet at a concentration of 10 ppm and 100 ppm, respectively, 9 days before the first carcinogen dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors and estimation of latency period, tumor frequency per group and animal, and tumor volume were recorded. The experiment was terminated 16 weeks after the first carcinogen dose, basic tumor growth parameters and selected metabolic and hormonal variables were evaluated. Chemoprevention with higher rosiglitazone dose decreased tumor frequency per group by 44%, other tumor parameters (incidence, tumor frequency per animal) were decreased insignificantly (at both doses), latency period was not changed. Rosiglitazone administration decreased cumulative tumor volume, more efficiently at lower dose. Glycaemia and insulinaemia decreased after lower rosigitazone dose administration but glycaemia did not exceed normal values. Higher rosiglitazone dose alleviated some metabolic alterations resulting from cancer progression more effectively but induced a prominent cardiac hypertrophy.

Immunohistochemical and histomorphological analysis of rat mammary tumors after simvastatin treatment.

The results of experimental studies have indicated the pleiotropic effects of statins in organism, e.g. the influence on cell cycle, apoptosis or angiogenesis. In this study, the effects of simvastatin on selected parameters of apoptosis and proliferation in chemocarcinogen-induced mammary tumorigenesis in female rats were determined. Simvastatin was administered dietary at a dose of 18 mg/kg and highly effective dose of 180 mg/kg the entire experiment (18 weeks). At autopsy mammary tumors were removed and prepared for immunohistochemical and histomorphological analysis. In treated animals (simvastatin 180 mg/kg), significant decrease by 12% in Bcl-2 protein expression and non-significant decrease by 27% of Ki67 protein expression in tumor cells compared to tumor cells in control animals were observed after semiquantitative evaluation. Morphometrical analysis has shown significant proapototic shift in Bcl-2/Bax ratio in tumor cells. In high grade control carcinoma cells, the expression of Ki67 increased by 37% (non-significantly) in comparison with control low grade carcinomas. A histomorphological analysis of malignant tumors has revealed a shift from high grade to low grade carcinomas after simvastatin treatment. The noticeable decrease of mammary tumor frequency and incidence in rats after simvastatin treatment was accompanied with antiapoptotic Blc-2 protein decrease and proapoptotic Bax protein increase in this experiment.

Melatonin enhanced bexarotene efficacy in experimental mammary carcinogenesis.

The aim of this paper was to test lower, safe bexarotene dose administered alone and in combination with melatonin to improve its efficacy. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea in female Sprague-Dawley rats, administered in two doses intraperitoneally between 42.-54. postnatal days and chemoprevention was initiated 7 days prior to first N-methyl-N-nitrosourea injection and lasted 15 weeks. Bexarotene, particularly in combination with melatonin decreased mammary tumor incidence and frequency with a shift from poorly to well differentiated carcinomas. Bexarotene alleviated glycaemia and liver/heart muscle glycogen concentration decreased as well as liver/thymus malondialdehyde increased in comparison with control group. The combination of bexarotene and melatonin is therefore beneficial in preventive-curative model of experimental mammary carcinogenesis and may be applied in oncological practice as such.

Antineoplastic effects of simvastatin in experimental breast cancer.

BACKGROUNDS: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have proven therapeutic and preventive effects on cardiovascular diseases. Preclinical evidence demonstrates tumor-suppressive effects of statins in several human neoplasias, including breast cancer. MATERIALS AND METHODS: In this study, antineoplastic effects of simvastatin in chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. The drug was dietary administered at two concentrations--18 mg/kg (SIMVA 18) and 180 mg/kg (SIMVA 180). RESULTS: Basic parameters of experimental carcinogenesis after long-term simvastatin treatment in animals were assessed. In the SIMVA 180 group, simvastatin significantly suppressed tumour frequency by 80.5% and tumour incidence by 58.5% in comparison to the controls. Higher dose simvastatin non-significantly decreased the mean tumor volume by 23.5%, as well as non-significantly lengthened the latency period by 14.5 days compared to the control animals. Simvastatin, administered at a lower dose did not change parameters of mammary carcinogenesis in comparison to the control group. Simvastatin in both treated groups significantly decreased serum levels of triacylglycerols and VLDL-cholesterol in comparison to the control animals. Compared to the controls, a significant increase in food intake by the animals was recorded in the SIMVA 18 and SIMVA 180 groups. No significant differences in the final body weight gain between the simvastatin-administered and the control group were found. CONCLUSION: This study represents the first report of simvastatin use in experimental mammary carcinogenesis in vivo.

Celecoxib and melatonin in prevention of female rat mammary carcinogenesis.

The present experiment aims to evaluate tumor suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2) celecoxib (Celebrex, Pfizer) administered alone and in combination with melatonin in the prevention of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in Sprague-Dawley female rats. Celecoxib was administered daily at a concentration of 1.666 g/kg diet to two groups during 20 weeks (starting a week before first NMU application). A combination of celecoxib and melatonin applied in drinking water (20 microg/ml drinking water), daily from 15:00 to 08:00 hours was administered to the second group. The anticarcinogenic effects of chemopreventive drugs were compared with control (NMU) animals. Celecoxib administration decreased mammary tumor incidence (by 24%), while combination of celecoxib and melatonin decreased tumor incidence even more significantly (-30%). Significant decrease in tumor frequency per group was recorded in both groups with chemoprevention: celecoxib alone (-54%) and combination of celecoxib and melatonin (-64%). Celecoxib significantly influenced tumor frequency per animal in the group with combination of both protective substances (-52%). Celecoxib administration resulted in prolonged latency by 3%, and by 13% in the group with combination of both protective substances. These results confirm preventive effects of celecoxib in induced rat mammary carcinogenesis. The administration of isolated MEL had only lesser effect, but in the combination with CELE revealed some potentiating influence in mammary carcinogenesis inhibition. The present study is the first to prove efficacy of the above-mentioned celecoxib and melatonin intake. Our results point to the need for a deeper analysis of coxib efficacy in human carcinogenesis.

Metformin in chemically-induced mammary carcinogenesis in rats.

In this paper the chemopreventive effect of peroral antidiabetic metformin in mammary carcinogenesis in female Sprague-Dawley rats was evaluated. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea (NMU) administered in two intraperitoneal doses each per 50 mg/kg b.w. between 43.-55. postnatal days. Metformin was administered in drinking water (at a concentration of 50 microg/ml and 500 microg/ml) 13 days before the first NMU dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors, the incidence, latency, tumor frequency, and tumor volume were recorded. The experiment was terminated 18 weeks after the first NMU dose, basic tumor growth parameters and metabolic and hormonal variables were evaluated. Metformin did not significantly alter the tumor growth although a delay in tumor onset was recorded after higher metformin dose. Metformin altered metabolic and hormonal variables. Insulinemia decreased after both metformin doses in comparison with intact rats without changes in glycemia, triacylglycerols concentration was decreased in liver and increased in serum when compared to intacts. Higher metformin dose attenuated lipoperoxidation in liver.

Prolonged melatonin administration in 6-month-old Sprague-Dawley rats: metabolic alterations.

The aim of this work was to evaluate the effect of prolonged melatonin administration on chosen metabolic and hormonal variables in male and female Sprague-Dawley rats. Melatonin was administered in tap water (4 microg/ml) daily from the 6th month of age. Rats were fed a standard type of diet ad libitum and were kept in a light regimen L:D--12:12h. The experiment was terminated after 12 weeks of melatonin administration. Melatonin decreased body mass during the whole experiment in females and from the 42nd day of the experiment in males. Relative heart muscle weight in females and absolute/relative thymus weight in males were increased after melatonin administration. Melatonin decreased glycaemia, heart muscle glycogen concentration in females and liver glycogen concentration in both sexes. Serum insulin concentration in males was decreased; serum corticosterone concentration was increased in both males and females. Serum triacylglycerol and heart muscle cholesterol concentration in females were decreased, however in males serum and heart muscle cholesterol concentration was increased. Liver phospholipid concentration in females was decreased and heart muscle phospholipid concentration in males was increased. Melatonin increased malondialdehyde concentration in heart muscle in males and in liver in both sexes. Melatonin induced prominent sex-dependent changes in both carbohydrate and lipid metabolism.

Effect of prolonged psychoemotional stress and melatonin on experimental mammary carcinogenesis in female rats.

The aim of the present study was to determine whether prolonged stress repeated immobilization in boxes during the period of 18 weeks (IMS) influenced development and progression of N-methyl-N-nitrosourea (NMU)-induced mammary tumors in female Sprague-Dawley rats and whether long-term MEL application affected changes caused by stress. NMU was applied intraperitoneally in two doses each of 50 mg/kg b.w. between 40-50 postnatal days. Melatonin (MEL) was administered in drinking water in a concentration of 4 microg/ml (daily from 3 p.m to 8 a.m), application was initiated 3 days prior to first NMU dose and lasted until the end of the experiment. Immobilization (2 h/day) began on the fifth day after second carcinogen application, animals were immobilized three times a week. Repeated immobilization of rats during 18 weeks decreased tumor frequency per group and per animal by 30% and tumor volume gain by 16% as opposed to control (NMU) animals. Combination of repeated immobilization and a long-term MEL application lowered incidence by 13% when compared to control, prolonged latency by 13%, decreased tumor frequency per group (by 44%) and per animal (by 35%). Tumor volume gain increased by 35% but their cumulative volume prominently decreased by 74% as opposed to control. Tumor volume was the most markedly influenced by MEL, induced tumors developed more rapidly tumor volume gain increased by 61%. However, their cumulative volume markedly decreased by 75% when compared to immobilized group drinking water. Prolonged stress inhibited development and progression of NMU-induced mammary gland tumors in female rats and this effect was enhanced by long-term melatonin administration.