BACKGROUND/AIM: Chemopreventive activity of a new probiotic strain Lactobacillus plantarum LS/07 (PRO) and prebiotic oligofructose-enriched inulin (PRE) in rat mammary carcinogenesis induced by procarcinogen 7,12-dimethylbenz[a]anthracene has been reported before. This study evaluated the anticancer and immunomodulatory efficacy of PRO, PRE, PRO+PRE (PRO/PRE) and combination with melatonin (PRO+PRE+MEL) in a rat model, when breast cancer was induced by a direct-acting carcinogen N-nitroso-N-methylurea (NMU). MATERIALS AND METHODS: Daily administration of PRO (at a dose of 8.4×10(8) colony-forming units (c.f.u.)/rat), PRE (in the diet, 20 g/kg) and MEL (in tap water, 20 mg/l) started 14 days before the first NMU dose and lasted for 16 weeks. RESULTS: Although tumor growth was not altered, a marked decrease in the ratio of high-/low-grade carcinomas and in tumoral Ki-67 expression was found after PRO+PRE treatment; melatonin augmented these effects. PRO+PRE+MEL combination enhanced CD4(+) and CD8(+) T-cell tumor infiltration induced by PRO/PRE and increased CD25(+)FoxP3(+) regulatory T-cells in tumors. CONCLUSION: In mammary carcinogenesis, Lactobacillus plantarum LS/07 and inulin exert prodifferentiating, antiproliferative and immunomodulatory activities, which are significantly amplified by melatonin co-administration.
- MeSH
- experimentální nádory mléčných žláz farmakoterapie MeSH
- imunologické faktory farmakologie MeSH
- interleukin-6 fyziologie MeSH
- inulin farmakologie MeSH
- krysa rodu rattus MeSH
- Lactobacillus plantarum * MeSH
- melatonin farmakologie MeSH
- methylnitrosomočovina MeSH
- potkani Sprague-Dawley MeSH
- probiotika farmakologie MeSH
- protinádorové látky farmakologie MeSH
- transformující růstový faktor beta1 fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The risk of cancer may be modulated by drugs with pleiotropic effects and diet has been implicated in the efficacy of treatment. The oncopreventive effects of the antidiabetic drug pioglitazone (PIO) and the anti-insomnia drug melatonin (MT), in vivo, have been proven before, but using a standard-type diet. This study evaluated the impact of a high-fat diet on their efficacy in chemically induced mammary carcinogenesis in Sprague-Dawley rats. Mammary tumours were induced by N-methyl-N-nitrosourea (50 mg/kg, intraperitoneal, on the 41st postnatal day). PIO and MT administration was initiated 11 days before the carcinogen application and lasted until the termination of the experiment at 16 weeks. PIO was administered in a diet (10% fat) at a concentration of 100 ppm and MT was administered in tap water (20 mg/l). PIO, MT and the combination did not significantly alter the basic tumour growth parameters. However, histopathology showed a decrease in the high-grade/low-grade tumour ratio, particularly in animals that received combined treatment (P<0.01). Semiquantitative immunohistochemistry indicated the proapoptotic effect of chemoprevention, particularly in the drug combination group (P<0.01), but no changes in tumour cell proliferation and angiogenesis were recorded. Results were evaluated by one-way analysis of variance or the Mann-Whitney U-test, respectively. PIO and MT, alone or in combination, administered to rats fed a high-fat diet reduced the proportion of high-grade tumours and promoted apoptosis in an in-vivo breast cancer model, although it did not suppress tumour growth. The impact of high dietary fat content on the chemopreventive efficacy of these and other substances should be considered in human studies.
- MeSH
- antioxidancia farmakologie MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- experimentální nádory mléčných žláz farmakoterapie etiologie patologie MeSH
- hypoglykemika farmakologie MeSH
- karcinogeny toxicita MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- melatonin farmakologie MeSH
- methylnitrosomočovina toxicita MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- thiazolidindiony farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Our previous results indicated significant tumor-suppressive effects of different statins in rat mammary carcinogenesis. The purpose of this experiment was to examine the chemopreventive effects of Pitavastatin alone and in combination with the pineal hormone melatonin in the model of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats. Pitavastatin was administered dietary (10mg/kg) and melatonin in an aqueous solution (20μg/ml). Chemoprevention began 7 days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Compared to controls, Pitavastatin alone reduced average tumor volume by 58% and lengthened latency by 8 days; on the other hand, the drug increased tumor frequency by 23%. Combined administration of Pitavastatin with melatonin decreased tumor frequency by 23%, tumor volume by 44% and lengthened tumor latency by 5.5 days compared to control animals. The analysis of carcinoma cells showed significant increase in caspase-3 expression in both treated groups and a tendency of increased caspase-7 expression after Pitavastatin treatment alone. Significant expression decrease of Ki67 was found in carcinoma cells from both treated groups. Compared to control carcinoma cells, Pitavastatin alone increased VEGF expression by 41%, however melatonin totally reversed its undesirable effect. Pitavastatin combined with melatonin significantly increased femur compact bone thickness in animals. Pitavastatin alone decreased plasma triglycerides and total cholesterol levels, however it significantly increased levels of glucose. In summary, our results show a partial antineoplastic effect of Pitavastatin combined with melatonin in the rat mammary gland carcinoma model.
- MeSH
- chinoliny terapeutické užití MeSH
- experimentální nádory mléčných žláz farmakoterapie MeSH
- krysa rodu rattus MeSH
- melatonin terapeutické užití MeSH
- nádory mléčné žlázy u zvířat farmakoterapie MeSH
- nádory prsu farmakoterapie MeSH
- protinádorové látky terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- chemoprofylaxe metody MeSH
- hodnotící studie jako téma MeSH
- karcinogeneze * genetika chemicky indukované patologie účinky léků MeSH
- lidé MeSH
- nádory prsu prevence a kontrola MeSH
- potkani Sprague-Dawley MeSH
- statiny * aplikace a dávkování terapeutické užití MeSH
- statistika jako téma MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
Východiská: Statíny (inhibítory 3-hydroxy-3-metylglutaryl koenzým A reduktázy) predstavujú látky s dobre dokumentovanými terapeutickými a preventívnymi účinkami u kardiovaskulárnych ochorení. V predklinických štúdiách statíny preukázali tumor-supresívne účinky u viacerých typov neoplázií vrátane rakoviny prsníka. Materiál a metódy: V tejto štúdii sme hodnotili antineoplastický účinok simvastatínu v chemoprevencii N-metyl-N-nitrozoureou – indukovanej mamárnej karcinogenézy u samíc potkanov. Farmakum bolo aplikované v potrave vo dvoch koncentráciách – 18 mg/kg (SIMVA 18) a 180 mg/kg (SIMVA 180). Výsledky: Po dlhodobej aplikácii simvastatínu sme na konci pokusu vyhodnotili základné parametre experimentálnej karcinogenézy. Simvastatín v skupine SIMVA 180 signifikantne znížil frekvenciu nádorov o 80,5 % a incidenciu nádorov o 58,5 % v porovnaní s kontrolou. Simvastatín v tej istej skupine zvierat nesignifikantne znížil priemerný objem nádorov o 23,5 % a nesignifikantne predĺžil latenciu o 14,5 dňa v porovnaní s kontrolnými zvieratami. U simvastatínu podávaného v nižšej dávke sme nepozorovali antineoplastické účinky. Simvastatín v oboch liečených skupinách signifikantne znížil sérové hladiny triacylglycerolov a VLDL-cholesterolu v porovnaní s kontrolnými zvieratami. V porovnaní s kontrolami sme v skupinách SIMVA 18 a SIMVA 180 pozorovali signifikantný nárast príjmu potravy u zvierat. Signifikantné zmeny prírastku telesnej hmotnosti medzi skupinami so simvastatínom a kontrolnou skupinou neboli zistené. Záver: Táto štúdia je prvou zmienkou o simvastatíne použitom v experimentálnej mamárnej karcinogenéze in vivo.
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.
- MeSH
- experimentální nádory mléčných žláz farmakoterapie chemicky indukované prevence a kontrola MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- potkani Sprague-Dawley MeSH
- protinádorové látky terapeutické užití MeSH
- simvastatin terapeutické užití MeSH
- statiny terapeutické užití MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
Nová generácia inhibítorov aromatázy predstavuje v súčasnosti prvú voľbu v endokrinnej liečbe pokročilého karcinómu prsníka u postmenopauzálnych pacientiek. Tieto farmaká sú rovnako účinné aj v adjuvantnej a neoadjuvantnej liečbe, výsledky niekoľkých prebiehajúcich štúdií môžu poukázať na ich úlohu v chemoprevencii rakoviny prsníka. Okrem toho sú potrebné dlhodobejšie štúdie, ktoré by dôsledne objasnili nežiaduce účinky inhibítorov aromatázy na ľudský organizmus. Účinnosť a bezpečnosť samostatne aplikovaných inhibítorov aromatázy u premenopauzálnych pacientiek s rakovinou prsníka je neznáma, v tejto oblasti bude potrebný ďalší výskum. Kombinované podávanie agonistov hormónu uvoľňujúceho luteinizačný hormón s inhibítormi aromatázy rozširuje využitie endokrinnej liečby rakoviny prsníka u premenopauzálnych žien či už s metastatickou alebo včasnou formou ochorenia. Výsledky našich štúdií chemoprevencie mamárnej karcinogenézy u samíc potkanov poukázali na potenciálnu výhodnosť aplikácie inhibítorov aromatázy – anastrozolu a letrozolu u premenopauzálnych žien postihnutých rakovinou prsníka.
The new generation of aromatase inhibitors has become the first choice of endocrine treatment of advanced breast cancer in postmenopausal patients. These compounds are also very effective as adjuvant and neoadjuvant treatment; results of several ongoing trials might elucidate their role in chemoprevention of breast cancer. Further studies with longer follow-up are required to provide a thorough evaluation of their safety profile. The effectiveness and safety of aromatase inhibitors as monotherapy in premenopausal breast cancer patients is unknown; this is an area for future research. Combined use of luteinising hormone releasing hormone agonists and aromatase inhibitors extends the use of endocrine therapy in premenopausal women with a metastatic or an early stage breast cancer. Our results of chemoprevention of mammary carcinogenesis in female rats have indicated potentially favourable effects of aromatase inhibitors – anastrozole and letrozole – in premenopausal women affected by breast cancer.
- MeSH
- estrogeny sekrece MeSH
- inhibitory aromatasy farmakologie terapeutické užití MeSH
- kombinovaná farmakoterapie metody MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- nádory prsu farmakoterapie MeSH
- postmenopauza metabolismus účinky léků MeSH
- premenopauza metabolismus účinky léků MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
