Sequential modifications of topoisomerase I activity in a camptothecin-resistant cell line established by progressive adaptation

摘要: The DNA-topoisomerase I (Topo I) inhibitor, camptothecin (CPT), is a plant alkaloid with an important antitumor activity. In order to investigate the cellular mechanism leading development of resistance this agent, we have established by progressive adaptation P388 subline resistant CPT. After 5 months continuous drug exposure, index reached value 20 and cell line, P388CPT0.3, was maintained in presence CPT-induced single strand breaks measured alkaline elution were found drastically reduced line. Topo activity DNA cleavage on cells at different steps resistance. We first observed that strongly decreased. addition, recovered ATP-independent relaxation after 3 exposure CPT, but still kept cleavage. Further evaluations final stage induction indicated presented CPT-resistant form I. Rearranged gene one allele transcription also cells. putative role rearrangement discussed. These data show has evolved from decreased altered enzyme, suggest multiple mechanisms modifications could contribute CPT