DIFFERENTIAL CYTOTOXICITY OF CLINICALLY IMPORTANT CAMPTOTHECIN DERIVATIVES IN P-GLYCOPROTEIN OVEREXPRESSING CELL-LINES

Camptothecin and its derivatives are specific inhibitors of eukaryotic topoisomerase I (top1) and are active in cancer patients against a va riety of refractory solid tumors and leukemia. Purpose: The present st udy further investigated the relationship between multidrug resistance (MDR) mediated by P-glycoprotein(MDR) and potential resistance to cam ptothecin derivatives using two experimental systems: (1) MDR KB-V1 ce lls selected for vinblastine resistance, and (2) NIH3T3 cells transfec ted with a plasmid expressing wildtype P-glycoprotein(MDR) multidrug t ransporter (NIH-MDR-G185). Results: We found that both KBV-1 and NIH-M DR-G185 cells were resistant to topotecan, and that topotecan-induced cleavable complexes were reduced in KB-V1 cells, consistent with a rol e of P-glycoprotein(MDR) in cellular resistance to topotecan. By contr ast, no significant resistance to camptothecin, 9-aminocamptothecin, 1 0, 11-methylenedioxycamptothecin, or SN-38 (the active metabolite of C PT-I1) was observed in NIH-MDR-G185 cells, while KB-V1 cells were cros s-resistant to these compounds but produced cleavable complexes simila r to those produced by parental KB-3-1 cells. Conclusions: These resul ts suggest that topotecan is the only camptothecin tested with signifi cant susceptibility to MDR in cell culture, and that multidrug resista nt cells such as KBV1 probably exhibit additional resistance mechanism s to camptothecins besides P-glycoprotein(MDR) overexpression.