Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells.

摘要: In order to understand the high efficacy of camptothecin derivatives against human colon tumor xenografts in nude mice, we have studied transport properties across cellular membranes MDR1-overexpressing cells. MDR1 overexpression was shown little effect on cytotoxicity; equally cytotoxic both drug-sensitive parental cell line, KB 3-1, and its multidrug-resistant derivative, V1. The ability overcome MDR1-mediated resistance is most likely due unimpaired accumulation cells as suggested from following experiments: (a) cytotoxicity V1 not altered by known MDR1-reversing agent, verapamil; (b) ineffective compared with vinblastine competing [3H]azidopine for photoaffinity labeling MDR1; (c) efficient trapping topoisomerase I molecules chromosomal DNA form cleavable complexes 3-1 mechanism which overcomes has been further using a number uncharged charged derivatives. contrast derivatives, such 9-amino-camptothecin 10,11-methylenedioxy-camptothecin, topotecan, showed reduced topotecan since verapamil restored cytotoxicity. These results suggest that charge can affect drug's sensitivity MDR1. possible membrane permeability determining drug selectivity discussed.