In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells.
In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells.
复制标题
临床上重要的喜树碱类似物对多重耐药细胞的体外和体内影响。
作者：
Mattern Mr;Glenn A. Hofmann;Polsky Rm;Funk Lr;F. L. McCabe;R. Johnson
评价了细胞毒性生物碱喜树碱（CPT）及其几种类似物（包括临床相关的拓扑替康（TPT）、伊立替康（CPT-11）和9-氨基喜树碱）在多药敏感（CIB 1）和多药耐药（MDR）（CHRC 5）中国仓鼠卵巢细胞中的不同细胞毒性作用和DNA损伤诱导。CPT、10-羟基喜树碱和10，11-亚甲二氧基喜树碱在两种细胞系中产生等量的细胞生长抑制和/或DNA单链断裂。TPT，SN-38（CPT-11的活性代谢产物）和9-氨基喜树碱对MDR的毒性分别为野生型细胞的12倍，9倍和10倍。这些发现与通过与各种化合物孵育2小时而在IB 1和CHRC 5细胞中产生的DNA单链断裂的产率的差异一致。在这两种试验中，拓扑异构酶I抑制剂的耐药率约为已知MDR药物（如长春碱或安吖啶）的十分之一。因此，过表达P-糖蛋白的培养细胞有可能对目前临床上所有三种拓扑异构酶I抑制剂产生一定程度的交叉耐药性。培养的MDR细胞系对某些CPT类似物的交叉耐药性的化学基础尚不清楚，但可能比单独的正电荷更复杂。TPT对移植P388白血病多药耐药亚系的B6 D2 F1雌性小鼠有较好的治疗作用，而对移植野生型P388细胞的小鼠无明显治疗作用。（250字处删节）
The cytotoxic alkaloid camptothecin (CPT) and several of its analogues, including the clinically relevant topotecan (TPT), irinotecan (CPT-11), and 9-aminocamptothecin, were evaluated for differential cytotoxic effect and DNA damage induction in multidrug-sensitive (AuxB1) and multidrug-resistant (MDR) (CHRC5) Chinese hamster ovary cells. CPT, 10-hydroxycamptothecin, and 10,11-methylenedioxycamptothecin produced equivalent amounts of cell growth inhibition and/or DNA single-strand breakage in the two cell lines. TPT, SN-38 (the active metabolite of CPT-11), and 9-aminocamptothecin were 12-, 9-, and 10-fold, respectively, less toxic to the MDR than to the wild-type cells. These findings are consistent with differences in yields of DNA single-strand breaks produced in AuxB1 and CHRC5 cells by 2-hr incubations with the various compounds. In both assays, the resistance ratios of the topoisomerase I inhibitors were approximately one-tenth those of known MDR drugs such as vinblastine or amsacrine. Thus, cultured cells that overexpress P-glycoprotein have the potential to develop some level of cross-resistance to all three topoisomerase I inhibitors currently in the clinic. The chemical basis for cross-resistance of cultured MDR cell lines to certain CPT analogues is not yet understood, but is likely more complex than positive charge alone. TPT had a reasonable therapeutic effect on B6D2F1 female mice implanted with MDR sublines of P388 leukemia, compared with its effect on mice implanted with wild-type P388 cells.(ABSTRACT TRUNCATED AT 250 WORDS)