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Kassayova M., E. Adamekova, B. Bojkova, P. Kubatka, I. Ahlers, E. Ahlersova: Effect of a Short-Term and Long-Term Melatonin Administration on Mammary Carcinogenesis in Female Sprague-Dawley Rats Infl uenced by Repeated Psychoemotional Stress. Acta Vet. Brno 2007, 76: 371-377. The aim of this study was to evaluate the effect of melatonin (MEL) on N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in female Sprague-Dawley rats exposed to repeated psychoemotional stress - immobilization in boxes. NMU was applied intraperitoneally in two doses each of 50 mg/kg b.w. between 40 - 50 postnatal days. Melatonin was administered in drinking water at a concentration of 4 μg/ml daily from 15:00 h to 8:00 h. The application was initiated 5 days prior to the fi rst NMU dose and lasted 15 days, i.e. during the promotion phase of tumour development, or long-term until the end of the experiment (week 20). Immobilization (2 h per day) began on the third day after the second carcinogen application and lasted for 7 consecutive days. Short-term MEL administration to immobilized animals increased incidence by 22%, decreased tumour frequency per animal by 26% and reduced tumour volume gain (by 21%) when compared to the immobilized group without MEL application. Decreased frequency per animal by 28% and more than a 40% decrease in tumour volume gain and cumulative volume were the most pronounced changes in the animals drinking MEL until the end of the experiment. Long-term MEL administration reduced the number and size of mammary tumours more markedly than its short-term administration. Melatonin decreased certain attributes of mammary carcinogenesis in female rats infl uenced by psychoemotional stress. Melatonin, mammary carcinogenesis, psychoemotional stress - restraint, rat

Orendas P., I. Ahlers, P. Kubatka, E. Ahlersova, B. Bojkova, M. Kassayova, L. Friedmanova, J. Kiskova, I. Ďatelinka, M. Starostova: Etoricoxib in the Prevention of Rat Mammary Carcinogenesis. Acta Vet. Brno 2007, 76: 613-618. Several experimental studies suggest that non-steroidal antiinflammatory drugs have chemopreventive effects in mammary carcinogenesis. In this study, tumour suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2) etoricoxib in the prevention of N-methyl-Nnitrosourea (NMU)-induced mammary carcinogenesis in Sprague-Dawley rats were evaluated. Etoricoxib was administered in the diet, at two concentrations: 1) 0.01 mg/g (ETO 0.001%) and 2) 0.025 mg/g (ETO 0.0025%). Although the chemopreventive effects were not statistically significant, remarkable tumour suppressive effects with the concentration of ETO 0.0025% were recorded. The incidence decreased by 4.31% and tumour frequency per group decreased by 6.67% when compared to the control group. Latency (the period from carcinogen administration to the first tumour appearance) increased by 7.28% in dose-dependent manner. The results of our experiments point to dose-dependent tumour suppressive effects of a higher concentration of etoricoxib (ETO 0.0025%) when compared to the control group. They suggest that higher etoricoxib concentrations may enhance its tumour suppressive effects.

Bojkova B., M. Markova, E. Ahlersova, I. Ahlers, E. Adamekova, P. Kubatka, M. Kassayova: Metabolic Effects of Prolonged Melatonin Administration and Short-Term Fasting in Laboratory Rats. Acta Vet. Brno 2006, 75: 21-32. The aim of this work was to evaluate the effect of prolonged administration of the pineal hormone melatonin and short-term fasting on metabolic variables in male and female Wistar:Han rats. Melatonin (MEL, 4µg/ml of tap water) was administered daily since the 5th week of age. The control group drank tap water. Rats were fed a standard type of diet ad libitum and were kept in the light regimen L:D – 12:12 h. The experiment was terminated after 11 (variant B) or 12 (variant A) weeks of MEL administration. The animals were sacrificed by quick decapitation following overnight fasting (variant A) or 48-h fasting (variant B). Selected organs and tissues were removed and weighed and selected metabolic variables in the serum and tissues were determined. MEL decreased body mass independent of food and water intake in both sexes. In males (variant A) MEL increased the weight of the heart muscle, spleen and adrenals; it decreased the absolute weight of epididymal fat and increased serum corticosterone and phospholipids concentration in comparison with controls. In females, serum glucose decrease and liver triacylglycerols increase were found. After 48-h fasting (variant B) liver, spleen and adrenal weight increase in MELdrinking females was found. In males MEL increased the thymus weight and decreased the epididymal fat weight. In both sexes MEL increased serum corticosterone and liver glycogen concentration; MEL increased serum glucose in males and serum cholesterol concentration in females. Changes in the evaluated variables were also related to fasting duration prior to decapitation. A 48-h fasting at the end of the prolonged MEL intake (variant B vs. A) decreased the absolute liver weight in both sexes and the epididymal/periovarial fat weight, and increased thymus weight in males. In females it decreased the absolute heart muscle weight and increased the spleen weight. In males, 48-h fasting increased serum corticosterone and phospholipids concentration; it decreased the liver triacylglycerols content in females and the liver cholesterol content in males and females. In both sexes 48-h fasting increased glucose concentration in the serum and glycogen concentration in the liver and heart muscle as well as triacylglycerols and cholesterol concentration in the serum, phospholipids concentration in the liver and bone marrow and decreased malondialdehyde concentration in the liver. Forty-eight hour fasting after prolonged MEL administration resulted in a wider range of carbohydrate and lipid metabolism alterations of young rats of both sexes. Melatonin, prolonged administration, metabolic variables, short-term fasting

Markova M., E. Adamekova, B. Bojkova, P. Kubatka, M. Kassayova, E. Ahlersova, I. Ahlers: Effect of Low-dose Chronic Melatonin Administration on Metabolic and Hormonal Variables in Young Laboratory Rats. Acta Vet. Brno 2004, 73: 445-453. The introduction of melatonin (MEL) as a drug remains open due to insufficient data about the effects of its long-term administration on metabolism. We explored effects of MEL given for 26 weeks at low doses, 4 µg/ml of tap water, on selected metabolic and hormonal indices in young female and male Sprague-Dawley rats. Male and female rats aged 5 weeks were adapted to standard housing conditions and artificial light regimen L:D = 12:12 h. The animals were fed standard laboratory diet and drank tap water (controls) or MEL solution ad libitum. Body weight gain, food and water intake was regularly recorded. Oral glucose tolerance tests (OGTTs) were carried out before and 24 weeks after MEL administration. At the end of the experiment following an overnight fast the animals were sacrificed, selected organs and tissues were weighed, selected metabolic indices and hormone concentrations were determined in the serum, liver, heart muscle and bone marrow (femur). Chronic MEL administration increased in females serum corticosterone concentration, decreased glycogen concentration in the liver and heart muscle, increased triacylglycerol concentration in the bone marrow. An increased absolute weight of periovarial fat and body weight gain were found in last 5 weeks of the experiment. In males, MEL decreased insulin concentration in the serum and body weight gain from week 2 to week 17 of its administration; it decreased relative liver weight in males and females. MEL did not alter food or water intake in both sexes. MEL treatment decreased glucose tolerance (i.e. reduced area under curve values in OGTTs) in males and prolonged the return of afterload glycemia values to initial level in females. Alterations of carbohydrate metabolism regulation and of body weigth gain were found in both sexes of young rats after long term melatonin administration.

Chamilova M., P. Kubatka, K. Kalicka, E. Adamekova, B. Bojkova, I. Ahlers, E. Ahlersova: Chemoprevention of N-methyl-N-nitrosourea Induced Mammary Carcinogenesis with Raloxifene and Melatonin: Metabolic Changes in Female Rats. Acta Vet. Brno 2002, 71: 235‐242. The aim of this work was to determine the selected parameters of carbohydrate and lipid metabolism in the mammary carcinogenesis induced with N-methyl-N-nitrosourea (NMU) in two doses, each by 50 mg/kg of body weight with a 7-day interval between them within the postnatal days 43 and 54 in female Sprague-Dawley rats. Chemoprevention started with the administration of melatonin (MEL, 4 µg/ml in water, from 15.00 h to 08.00 h) 12 days and raloxifene (RAL 5 mg/kg, 2 × weekly) 10 days before the application of NMU. Twenty-four weeks following the NMU administration the animals were killed, and the incidence, latency, frequency and volume of tumours were evaluated. The animals were divided into: tumour-bearing (TB) and non-tumourbearing (NTB) with the influence of RAL, MEL and their combination. While RAL and RAL plus MEL significantly decreased the incidence and frequency of tumours, the effect of isolated MEL was substantially lower. In the serum, an increase in the concentration of serum glucose in TB and also NTB animals was observed. In the liver of both the TB and NTB animals, the content of cholesterol (CH) and triacylglycerols (TG) decreased and the contents of phospholipids (PL) increased. RAL decreased the contents of CH and PL in the liver of NTB animals and increased the concentration of TG in both groups of animals. Administration of RAL to NTB animals decreased the concentrations of malondialdehyde (MDA) in the serum and thymus, in the bone marrow also in TB animals. MEL decreased the concentration of MDA in the bone marrow of TB animals. MEL increased the concentrations of serum glucose and glycogen content in the heart muscle of NTB animals. RAL plus MEL decreased the concentration of serum TG and PL and decreased the contents of CH and PL in the liver of TB as well as NTB animals. In the thymus and liver, combination of RAL+MEL decreased the MDA content compared with the RAL alone in NTB animals. The co-effect of two or more substances will be probably the optimal way in prevention of cancer. The co-effect of RAL and MEL shows to be a prospective way for influencing the mammary tumors. Breast cancer, female rats, raloxifene, melatonin, chemoprevention

Chamilova M., B. Bojkova, K. Kalicka, P. Kubatka, E. Adamekova, E. Ahlersova, I . A hlers, B . P astorova: Retinyl Acetate and Melatonin in Chemoprevention of Mammary Carcinogenesis in Female Rats: Metabolic Changes. Acta Vet. Brno, 2001, 70: 57-63. Combination of chemopreventive substances is expected to be an effective way to combat cancer in the near future. We therefore tested the effect of retinyl acetate (RA) and melatonin (MEL). Nmethyl-N-nitrosourea (MNU) was used to induce mammary carcinogenesis in female SpragueDawley rats (n = 71). NMU was administered intraperitoneally in two doses, each of 50 mg/kg b.w. between postnatal days 43 and 57. MEL was given in drinking water (20 µg/ml) to group 1 (n = 18) for 22 weeks, beginning 12 d before NMU administration. RA administration (8.2 mg per animal and day per os) in group 2 (n = 18) started 11 days before NMU administration and lasted for 22 weeks. Group 3 (n = 17) received both chemopreventive substances and group 4 (n = 10) was left intact. The incidence, latency period, frequency and tumor volume were evaluated in all animals. Selected indices of carbohydrate and lipid metabolism were evaluated in tissue samples and blood serum. RA+MEL combination decreased the incidence and frequency per group and lengthened the latency period for tumor occurrence. Both MEL and RA+MEL decreased the serum glucose concentration in tumor-bearing (TB) as well as in non-TB (NTB) animals. In TB animals a decrease of serum cholesterol (CH) in comparison with NTB and intact animals was observed. In the liver of both TB and NTB animals, RA administration led to CH accumulation, RA+MEL combination did not influence this situation. MEL alone and in combination with RA markedly decreased the malondialdehyde concentration in bone marrow of both TB and NTB animals. The combination of RA + MEL extended the possibilities of a succesfull prevention of experimental mammary carcinogenesis. MEL did not cause substantial side effects in the chronic administration protocol and the decrease in tissue lipid peroxidation predominated among its effects.