Prostate cancer treatment costs increase more rapidly than for any other cancer-how to reverse the trend?

According to GLOBOCAN, about 1.41 million new prostate cancer (PCa) cases were registered in the year 2020 globally. The corresponding socio-economic burden is enormous. Anti-cancer mRNA-based therapy is a promising approach, the principle of which is currently applied for anti-COVID-19 vaccination, undergoing a detailed investigation in populations considering its short- and long-term effectiveness and potential side effects. Pragmatically considered, it will take years or even decades to make mRNA therapy working for any type of cancers, and if possible, for individual malignancy sub-types which are many specifically for the PCa. Actually, the costs of treating PCa are increasing more rapidly than those of any other cancer. The trend has to be reversed now, not in a couple of years. In general, two main components are making currently applied reactive (management of clinically manifested disease) PCa treatment particularly expensive. On one hand, it is rapidly increasing incidence of the disease and metastatic PCa as its subtype. To this end, rapidly increasing PCa incidence rates in young and middle-aged male sub-populations should be taken into account as a long-term contributor to the metastatic disease potentially developed later on in life. On the other hand, patient stratification to differentiate between non-metastatic PCa (no need for an extensive and costly treatment) and particularly aggressive cancer subtypes requiring personalised treatment algorithms is challenging. Considering current statistics, it becomes obvious that reactive medicine got at its limit in PCa management. Multi-professional expertise is unavoidable to create and implement anti-PCa programmes in the population. In our strategic paper, we exemplify challenging PCa management by providing detailed expert recommendations for primary (health risk assessment), secondary (prediction and prevention of metastatic disease in PCa) and tertiary (making palliative care to the management of chronic disease) care in the framework of predictive, preventive and personalised medicine.

Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention.

Cancerous tissue transformation developing usually over years or even decades of life is a highly complex process involving strong stressors damaging DNA, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk within the neighboring tissues. Only the minor part of all cancer cases are caused by inborn predisposition; the absolute majority carry a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Amongst most promising candidates for dietary supplements are bioactive phytochemicals demonstrating strong anticancer effects. Abundant evidence has been collected for beneficial effects of flavonoids, carotenoids, phenolic acids, and organosulfur compounds affecting a number of cancer-related pathways. Phytochemicals may positively affect processes of cell signaling, cell cycle regulation, oxidative stress response, and inflammation. They can modulate non-coding RNAs, upregulate tumor suppressive miRNAs, and downregulate oncogenic miRNAs that synergically inhibits cancer cell growth and cancer stem cell self-renewal. Potential clinical utility of the phytochemicals is discussed providing examples for chemoprevention against and therapy for human breast cancer. Expert recommendations are provided in the context of preventive medicine.

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.

[Neoplastic effect of indomethacin in N-methyl-N-nitrosourea induced mammary carcinogenesis in female rats]. / Neoplastické úcinky indometacínu v N-metyl-N-nitrozoureou indukovanej mamárnej karcinogenéze u samíc potkanov.

BACKGROUND: High levels of prostaglandins found in many neoplastic tissues, especially in colon cancer and breast cancer, suggest a role of cyclooxygenase in the process of carcinogenesis. MATERIAL AND METHODS: The aim of this study was to analyse the chemopreventive potential of non-steroidal inflammatory drug indomethacin and its combination with pineal hormone melatonin in rat mammary carcinogenesis induced by N-methyl-N-nitrosourea. Indomethacin was administered 3 times a week and melatonin 4 times a week, both substances in a concentration of 20 µg/ml of drinking water. Chemoprevention began approximately 2 weeks before carcinogen administration and lasted until the end of the experiment 25 weeks later. RESULTS: Indomethacin administered alone and in combination with melatonin stimulated the growth of mammary tumors. We found a significant increase in the average tumor volume caused by indomethacin alone by 126%, and in combination with melatonin by 104% compared to the control group. Indomethacin administered alone increased the incidence of tumors by 21.5% (also in combination with melatonin) and reduced the tumor latency by 17 days compared to controls. Melatonin alone significantly reduced tumor volume in comparison with control animals. During the long-term administration, both substances were well tolerated by animals. CONCLUSION: Indomethacin, a predominant cyclooxygenase inhibitor-1, showed significant neoplastic effects in the prevention of N-methyl-N-nitrosourea induced rat mammary carcinogenesis. This finding is in strong contrast to our previous experiment, where indomethacin in 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis revealed marked antineoplastic effects.

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.

[Evaluation of aromatase inhibitors' side effects in clinical and experimental studies]. / Hodnotenie vedl'ajsích ucinkov inhibítorov aromatázy v klinických a experimentálnych stúdiách.

Aromatase inhibitors are now the first choice endocrine therapy in the metastatic setting for postmenopausal women.These endocrine agents also seem likely to soon become the standard adjuvant therapy for postmenopausal patients with hormone-responsive breast cancer, either alone or in sequence with tamoxifen. In the treatment with aromatase inhibitors, the incidence of some adverse effects such as endometrial cancer, stroke or pulmonary tromboembolism treatment associated with tamoxifen is reduced. Questions remain about the long-term side-effects and safety profile of aromatase inhibitors--monitoring and handling of bone loss associated with their application are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of aromatase inhibitors on lipid metabolism and cardiovascular health.

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.

Side effects of anastrozole in the experimental pre-menopausal mammary carcinogenesis.

UNLABELLED: The aim of this study was to assess side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats. This model mimicked situation in healthy, but from the point of view of the development of breast cancer, high-risk pre-menopausal women.

Aromatase inhibitor anastrozole was used as a chemopreventive agent taken by the animals in the food during the whole period of time of the experiment. Group 1 - the control group had taken food without anastrozole, the groups 2 and 3 with anastrozole in various concentrations - 0.05 mg/1 kg of food (ANA 0.05) and 0.5 mg/1 kg of food (ANA 0.5).

In anastrozole-treated animals in comparison with untreated animals, macroscopic changes of uterus and vagina were not found. The values of absolute and relative wet weight of uterus and vagina in the groups ANA 0.05 and ANA 0.5 were comparable with the control. Histological examination did not show atrophic changes in endometrium of uterus and in epithelium of vagina in anastrozole-treated animals. In the group ANA 0.5 myometrium was significantly grosser than in the group ANA 0.05 (P<0.05). Anastrozole neither affects parameters of plasma lipid metabolism (triacylglycerols, total cholesterol, low - density lipoprotein cholesterol and high - density lipoprotein cholesterol) nor serum levels of sex hormones (estradiol, testosterone, dehydroepiandrosterone). Compact bone thickness in the groups with anastrozole was significantly increased in comparison with untreated animals (P<0.001). A significant increase in body weight was found in the group ANA 0.5 compared with the control group (P<0.01). The significant increase in body weight gain was not attended by the significant increase in food intake.

The side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats on myometrium, compact bone thickness and body weight gain were observed.

[Aromatase inhibitors in risk reduction of breast cancer: potential use in premenopausal women]. / Inhibítory aromatázy v prevencii rakoviny prsníka: moznosti aplikácie u premenopauzálnych zien.

Aromatase inhibitors are effective and well tolerated drugs in the endocrine therapy of estrogen-receptor positive breast cancer in postmenopausal women. Questions remain about the long-term side effects and safety profile of aromatase inhibitors. The results of ongoing studies may indicate the role of aromatase inhibitors in the prevention of breast cancer. The effectiveness and safety of aromatase inhibitor monotherapy in premenopausal breast cancer patients is unknown, so this is an area of future exploration. Our results in the chemoprevention of mammary carcinogenesis in female rats pointed to the potential favourable effects of aromatase inhibitors--anastrozole and letrozole in premenopausal women affected by breast cancer.

Neoplastic effects of exemestane in premenopausal breast cancer model.

Aromatase inhibitor exemestane as a single - agent has no established role in the treatment of premenopausal breast cancer women. The aim of this study was to evaluate preventive effects of exemestane in the model of premenopausal Nmethyl- N-nitrosourea - induced mammary carcinogenesis in female rats. Exemestane treatment begun 7 days prior to carcinogen administration and continued next 12 weeks - till the end of experiment. Exemestane was dietary administered in two concentrations of 1 mg / 1kg (EXE 1), or 10 mg/1 kg (EXE 10), respectively. Exemestane increased the tumor frequency by 80.5 % (P=0.034) in the group EXE 1 and by 61.5 % (P=0.045) in the group EXE 10 in comparison with control animals. In the group EXE 10, the incidence of mammary tumors was increased by 11.5 % (P=0.31) and tumor volume by 41.5 % (P=0.23), also the latency was shortened by 8 days (P=0.078) compared with controls. In the groups with exemestane, changes in weights and histology of uterus and vagina were not found at the end of experiment. Exemestane did not alter serum concentrations of estradiol, testosterone and dehydroepiandrosterone. In the group EXE 10 in comparison with untreated animals, exemestane decreased serum concentrations of triacylglycerols by 9 % (P=0.032), total cholesterol by 19.5 % (P=0.0002) and cholesterol of low - density and high - density lipoprotein fractions by 41 % (P<0.0001), or 21.5 % (P=0.0002), respectively. In the group EXE 1, the decrease in cholesterol of low-density lipoprotein fraction by 22.5 % (P=0.0005) was recorded. An increase in food intake (P=0.023) and body weight gain (P=0.036) was found in the group EXE 10 compared with the control group (P<0.05). The present study points to apparent tumor - promoting effects of dietary administered exemestane in the model of premenopausal mammary carcinogenesis in female rats. Exemestane as a steroidal agent indicated androgenic effects on rat lipid metabolism in this experiment.

Preventive effects of letrozole in the model of premenopausal mammary carcinogenesis.

Single - agent therapy with aromatase inhibitors has no established role in premenopausal women with breast cancer. In this study, tumor suppressive effects of letrozole in the prevention of N-methyl-N-nitrosourea - induced mammary carcinogenesis in female Sprague-Dawley rats were evaluated. Letrozole was dietary administered in two concentrations - 1 mg/1 kg (LETRO 1), and 10 mg/1 kg (LETRO 10). Letrozole suppressed incidence of mammary gland cancer by 93 % (P<0.00002) in the group LETRO 1 in comparison with control animals. Total suppression of mammary carcinogenesis was observed in the group LETRO 10. In the groups with letrozole, uterine and vaginal atrophy was found at the end of experiment. In letrozole - treated animals in comparison with untreated animals, increased plasmatic triacylglycerol concentrations (P<0.0001) were observed, but total cholesterol and cholesterol of low- and high- density lipoprotein fractions were not significantly changed. An increase in body weight gain and food intake was found in the groups LETRO 1 and LETRO 10 compared with the control group (P<0.0001). The present study points to high tumor suppressive effects of letrozole in premenopausal model of mammary carcinogenesis in female rats.

Aromatase inhibitors in the breast cancer therapy and their potential using in the prevention setting.

Long term exposure to estradiol is associated with an increased risk of breast cancer. Aromatase inhibitors, suppressing tumour and plasma estrogen levels by blocking conversion of testosteron to estrogen, have been proven to provide the most effective endocrine therapy in metastatic and adjuvant setting in postmenopausal women. Questions remains about the long term side effects and safety profile of aromatase inhibitors. The effectiveness and safety of aromatase inhibitors therapy in premenopausal breast cancer patients is unknown, this needs to be further investigated. Although tamoxifen represents the gold standard for prevention therapy at present, results of ongoing studies may indicate a role of aromatase inhibitors in prevention of breast cancer (Tab. 2, Ref. 22).

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.

NMU-induced mammary carcinogenesis in female rats is influenced by repeated psychoemotional stress.

Epidemiological and experimental studies indicate psychoemotional stress as an important factor in carcinogenesis. The aim of this study was to evaluate the effect of restraint stress on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis. Female Sprague-Dawley rats were injected with two intraperitoneal NMU doses each per 50 mg/kg b.w. between 39-49 postnatal days. Three experimental groups were created: 1. NMU (without restraint--control group, 12 animals), 2. NMU+1IMS (group with single restraint, IMS--immobilization stress, 12 animals), 3. NMU+7IMS (group restrained 7 times during a week, 12 animals). Animals were immobilized daily in special boxes for 120 minutes or 7 x 120 minutes, respectively from third day after carcinogen administration. The observation lasted for 20 weeks. The incidence, frequency, latency and volume of mammary tumors were evaluated. In repeatedly immobilized group NMU+7IMS increase in tumor incidence by 57% (p<0.05), marked increase in frequency per group by 153% (p<0.01), increase in frequency per animal by 61% and shortened latency period by 7 days were recorded. The effect of single restraint was not seen. In this experiment repeated immobilization carried out early after carcinogen administration had a remarkable stimulatory effect on chemically-induced mammary carcinogenesis in female rats.

Nimesulide and melatonin in mammary carcinogenesis prevention in female Sprague-Dawley rats.

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. Mamary tumors in female Sprague-Dawley rats were induced by N-methyl-N-nitrosourea (NMU) and by 7,12-dimethylbenz(a)anthracene (DMBA), 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 20microg/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 chemopreventives 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 DMBA-induced carcinogenesis an oncostatic effect of NIM was not observed; MEL administration 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 cholesterol content in the liver, triacyglycerol and phospholipid concentrations in the bone marrow and decreased malondialdehyde 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.

Variability of mammary carcinogenesis induction in female Sprague-Dawley and Wistar:Han rats: the effect of season and age.

It is important to determine and clarify the variability of mammary carcinogenesis induction in animal experimental studies particularly in connection with chemoprevention projects. The circannual seasonal rhythms of hormone levels or various parameters within the immune system may involve factors participating in mammary gland carcinogenesis. In our study, 19 experiments were conducted and all of them lasted for about 25 weeks after chemical carcinogen administration (DMBA or NMU) under standard laboratory conditions. Females of two rat strains - a medium susceptible Sprague-Dawley strain and a very low susceptible Wistar:Han were used. We observed not only the effect of seasonal changes but also the effect of age after single or repeated carcinogen administration. The seasonal dependence of mammary carcinogenesis with higher tumor incidence during long days in comparison with winter short days has been demonstrated in Sprague-Dawley rats. In experiments on the Wistar:Han strain, certain features of seasonal character were recorded, although the very low susceptibility of this strain to mammary carcinogenesis might have influenced the results. A limited period of carcinogen administration in early puberty around postnatal days 43-46 (higher susceptibility), when compared to the period after postnatal day 50, is the factor significantly increasing incidence and frequency of mammary carcinogenesis in the Sprague-Dawley strain. Our results indicate the need to consider the effect of season and age of animals at the time of carcinogen administration on rat mammary carcinogenesis induction. However, the application of the results obtained in one strain of experimental animals may only lead to misleading conclusions.

Preventive effects of raloxifene and melatonin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats.

The aim of this study was to evaluate preventive effects of raloxifene (RAL), melatonin (MEL) and their combination in N-methyl-N-nitrosourea (NMU)-induced rat mammary carcinogenesis. MEL-treatment began 12 days and RAL treatment began 10 days prior to carcinogen administration and continued till the end of experiment (24 weeks after first carcinogen administration). RAL was administered subcutaneously twice a week in the dose of 5 mg/kg b.w. MEL was administered diluted in drinking water in a concentration 4 microg/ml daily from 3 p.m. to 8 a.m. At the end of experiment, tumor incidence, frequency, latency period and tumor volume as parameters of mammary carcinogenesis were evaluated. Moreover, the effect of chemopreventives on body and uterine weight, food and water intake were recorded. In RAL-treated group, tumor incidence was decreased by 67% (p < 0.001), tumor frequency per group was reduced by 90% (p < 0.0002) and latency period lengthened by 27 days in comparison with control group. After MEL-treatment tumor incidence was decreased by 19%, tumor frequency per group was decreased by 50% (p < 0.05) when compared to control animals. The effect of RAL+MEL-treatment was very similar to that of RAL-treatment. In groups with RAL administration, significant decrease (p < 0.0001) in body weight gain and relative uterine weight was recorded. As to food intake no significant differences in comparison with control group were found. Consequently, groups were pooled and in RAL-treated groups (RAL, RAL+MEL) a decrease in food intake, when compared to groups without RAL administration (control group, MEL) was recorded (p<0.04). The water intake was markedly decreased in RAL-treated groups (P < 0.0001). RAL and RAL+MEL proved to be very effective in prevention of experimental mammary carcinogenesis in female rats, isolated MEL appeared to be of lower oncostatic activity.

Preventive effect of indomethacin and melatonin on 7, 12-dimethybenz/a/anthracene-induced mammary carcinogenesis in female Sprague-Dawley rats. A preliminary report.

The aim of the experiment was to analyse the oncostatic effect of nonsteroidal antiinflammatory drug INDO, hormone MEL and combination of both substances in DMBA-induced mammary carcinogenesis in female SD rats. Chemoprevention started 10 days before the application of the first dose of DMBA to 35-day-old rats. INDO was administered in tap water (20 microg/ml of water) for 3 days in a week (days 2, 4 and 6), MEL solution in the concentration of 20 microg/ml of tap water was administered between 3 p.m. and 8 a.m. for 4 days in a week (days 1, 3, 5 and 7); during other days the animals drank tap water only. In combined chemoprevention, rats were drinking solutions of INDO and MEL according to the above-mentioned scheme. DMBA in the dose of 10 mg/rat was administered intragastrically using a probe to all rats 3 times on postnatal days 45, 50 and 55. There were four experimental groups: group 1--without chemoprevention, group 2--INDO treatment, group 3 --MEL treatment, group 4--application of INDO + MEL. The experiment lasted 26 weeks from the first administration of DMBA, when the final incidence and frequency of tumours per animal and group, as well as latency and average volume of tumours were evaluated. The content/concentration of malondialdehyde (MDA) was determined in selected tissues as a criterion of lipoperoxidation, considering its potential influencing by chemoprevention. The tumour incidence in controls was 100%; INDO reduced the incidence (36.84%) and frequency per group and animal, decreased the mean volume of tumours and prolonged the latency. Chemoprevention using combination of INDO with MEL was successful like that with INDO; however, it did not influence the tumour volume. MEL decreased the incidence to 42.11% and pronouncedly reduced the tumour frequency per group. INDO, administered alone or in combination with MEL, reduced an increased content/concentration of MDA in the liver, bone marrow and serum of tumour-bearing rats. INDO, MEL and INDO + MEL had a pronounced chemopreventive effect and showed to be a favourable combination in prevention of experimental mammary carcinogenesis.