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1.
Toxicol Appl Pharmacol ; 272(2): 391-8, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23811332

RESUMO

The water disinfection byproduct bromate (BrO3(-)) produces cytotoxic and carcinogenic effects in rat kidneys. Our previous studies demonstrated that BrO3(-) caused sex-dependent differences in renal gene and protein expression in rats and the elimination of brominated organic carbon in their urine. The present study examined changes in renal cell apoptosis and protein expression in male and female F344 rats treated with BrO3(-) and associated these changes with accumulation of 3-bromotyrosine (3-BT)-modified proteins. Rats were treated with 0, 11.5, 46 and 308 mg/L BrO3(-) in drinking water for 28 days and renal sections were prepared and examined for apoptosis (TUNEL-staining), 8-oxo-deoxyguanosine (8-oxoG), 3-BT, osteopontin, Kim-1, clusterin, and p-21 expression. TUNEL-staining in renal proximal tubules increased in a dose-related manner beginning at 11.5mg BrO3(-)/L in female rats and 46 mg/L in males. Increased 8-oxoG staining was observed at doses as low as 46 mg/L. Osteopontin expression also increased in a dose-related manner after treatment with 46 mg/L, in males only. In contrast, Kim-1 expression increased in a dose-related manner in both sexes, although to a greater extent in females at the highest dose. Clusterin and p21 expression also increased in a dose-related manner in both sexes. The expression of 3-BT-modified proteins only increased in male rats, following a pattern previously reported for accumulation of α-2u-globulin. Increases in apoptosis in renal proximal tubules of male and female rats at the lowest doses suggest a common mode of action for renal carcinogenesis for the two sexes that is independent of α-2u-globulin nephropathy.


Assuntos
Apoptose/efeitos dos fármacos , Bromatos/toxicidade , Carcinógenos Ambientais/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Tirosina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Caracteres Sexuais , Tirosina/biossíntese
2.
Arch Biochem Biophys ; 515(1-2): 112-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21906582

RESUMO

Anthracyclines are potent anticancer agents, but cardiotoxicity mediated by free radical generation limits their clinical use. This study evaluated the anticancer activity of phenyl-2-aminoethyl selenide (PAESe) and its potential to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe with DOX, and vincristine, clinically used anticancer agents, and tert-butylhydroperoxide (TBHP), a known oxidant, on the growth of human prostate carcinoma (PC-3) cells was determined. PAESe (≤1µm) did not alter the growth of PC-3 cells, however, concomitant use of PAESe decreased the oxidative-mediated cytotoxicity of TBHP, but had limited effect on vincristine or DOX activity. Further, PAESe decreased the formation of intracellular reactive oxygen species from TBHP and DOX. The effect of PAESe on the activity of DOX was determined using a tumor (PC-3) xenograft model in mice. PAESe did not alter DOX antitumor activity and showed evidence of direct antitumor activity relative to controls. DOX treatment decreased mice body weight significantly, whereas concomitant administration of PAESe and DOX was similar to controls. Most importantly, PAESe decreased DOX-mediated infiltration of neutrophil and macrophages into the myocardium. These data suggest PAESe had in vivo antitumor activity and in combination with DOX decreased early signs of cardiotoxicity while preserving its antitumor activity.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Coração/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular , Feminino , Humanos , Masculino , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Biol Ther ; 12(5): 407-20, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21709443

RESUMO

PURPOSE: The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer. RESULTS: A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining. METHODS: The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model. CONCLUSIONS: These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Topotecan/uso terapêutico , Animais , Anexina A5/biossíntese , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Humanos , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/enzimologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Topotecan/administração & dosagem , Topotecan/farmacologia , Proteína Supressora de Tumor p53/biossíntese
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