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Gene ; 684: 30-38, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30315927

RESUMO

Anti-proliferative, anti-metastatic and anti-angiogenic effects of 17­allylamino­17­demethoxy geldanamycin (17-AAG) were studied alone and in combination with Capecitabine (Cap) and/or Irinotecan (IR) on HT-29 human colorectal carcinoma cells. Expression of MMP-9 (matrix metalloproteinase­9) and VEGF (vascular endothelial growth factor) mRNA was analyzed by real-time PCR method. The study was further followed by wound scratch assay for migration assessment. Nitric oxide content, Malondialdehyde generation and total anti-oxidant capacity were also assessed. Results showed significant differences between mono- and double therapy (p < 0.05). Combination of 17-AAG with IR or Cap resulted in synergistic effect (Combination Index < 1). Among double combination groups only Cap/17-AAG showed significant differences in MMP-9 and VEGF genes expression and wound healing assay. Moreover, a significant decrease of wound area in our triple combination group was obtained, indicating the antagonistic effect. IR/17-AAG and IR/Cap double combination groups resulted in down-regulation of MMP-9 and VEGF mRNA expression, respectively. Significant generation of MDA and decrease in TAC values have been observed in all our tested groups, however, the IR/17-AAG combination was the only group that could elevate NO concentration, significantly. Our findings demonstrated potent anti-angiogenesis and anti-metastatic effects for 17-AAG when it is provided in double combination especially with Cap, suggesting a new protocol in colorectal cancer combination therapy. These findings may indicate that down-regulation of VEGF and MMP-9 genes is directly related to angiogenesis and metastasis.


Assuntos
Benzoquinonas/metabolismo , Benzoquinonas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Camptotecina/análogos & derivados , Camptotecina/metabolismo , Capecitabina/metabolismo , Capecitabina/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Fluoruracila/análogos & derivados , Fluoruracila/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Humanos , Irinotecano/metabolismo , Irinotecano/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
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