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1.
Cancer Biol Ther ; 7(6): 822-32, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18340113

RESUMO

Irinotecan is a topoisomerase I inhibitor widely used as an anticancer agent in the treatment of metastatic colon cancer. However, its efficacy is often limited by the development of resistance. We have isolated a colon carcinoma cell line, HCT116-SN6, which displays a 6-fold higher resistance to SN38, the active metabolite of irinotecan. In this paper, we studied the molecular mechanisms that cause resistance to SN38 in the HCT116-SN6 cell line. First, we analyzed proliferation, cell cycle distribution, apoptosis, topoisomerase I expression and activity in SN38-resistant (HCT116-SN6) and sensitive (HCT116-s cells). We showed that the SN38-induced apoptosis and the SN38-activated cell cycle checkpoints leading to G(2)/M cell cycle arrest were similar in both cell lines. Topoisomerase I expression and catalytic activity were also unchanged. Then, we compared mRNA expression profiles in the two cell lines using the Affymetrix Human Genome GeneChip arrays U133A and B. Microarray analysis showed that among the genes, which were differentially expressed in HCT116-s and HCT116-SN6 cells, 27% were related to cell proliferation suggesting that proliferation might be the main target in the development of resistance to SN38. This result correlates with the phenotypic observation of a reduced growth rate in HCT116-SN6 resistant cells. Furthermore, 29% of the overexpressed genes were Interferon Stimulated Genes and we demonstrate that their overexpression is, at least partially, due to endogenous activation of the p38 MAP kinase pathway in SN38 resistant cells. In conclusion, a slower cell proliferation rate may be a major cause of acquired resistance to SN38 via a reduction of cell cycle progression through the S phase which is mandatory for the cytotoxic action of SN38. This lower growth rate could be due to the endogenous activation of p38.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Interferons/metabolismo , Apoptose , Camptotecina/farmacologia , Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , DNA Topoisomerases Tipo I/metabolismo , Humanos , Concentração Inibidora 50 , Irinotecano , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo
2.
Int J Cancer ; 109(6): 848-54, 2004 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-15027118

RESUMO

Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenocarcinoma/tratamento farmacológico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Antineoplásicos Fitogênicos/uso terapêutico , Colo/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , DNA Topoisomerases Tipo I/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Irinotecano , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , RNA Mensageiro/metabolismo , RNA Neoplásico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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