Camptothecin Overcomes MDR1-mediated Resistance in Human KB Carcinoma Cells

In order to understand the high efficacy of camptothecin derivatives against human colon tumor xenografts in nude mice, we have studied the transport properties of camptothecin derivatives across cellular mem branes of MDRl-overexpressing cells. MDR1 overexpression was shown to have little effect on camptothecin cytotoxicity; camptothecin was equally cytotoxic to both the drug-sensitive parental cell line, KB 3-1, and its multidrug-resistant derivative, KB VI. The ability of camptothecin to overcome MDRl-mediated resistance is most likely due to unimpaired accumulation of camptothecin in MDR1 cells as suggested from the following experiments: (a) cytotoxicity of camptothecin against KB VI cells was not altered by the known MDR 1-reversing agent, verapamil; (/<) camptothecin was ineffective as compared with vinblastine in com peting with pHjazidopine for photoaffmity labeling of \IDR1; (<) camp tothecin was equally efficient in trapping cellular topoisomerase I mole cules on chromosomal DNA in the form of cleavable complexes in both KB 3-1 and KB VI cells. The mechanism by which camptothecin overcomes MDRl-mediated resistance has been further studied using a number of uncharged and charged camptothecin derivatives. In contrast to the uncharged campto thecin derivatives, such as 9-amino-camptothecin and 10,11-methylenedioxy- camptothecin, the charged camptothecin derivative, topotecan, showed reduced cytotoxicity against MDRl-overexpressing KB VI cells. The reduced cytotoxicity of topotecan in KB VI cells was due to the overexpression of MDR1 in KB VI cells since verapamil restored both topotecan accumulation and cytotoxicity. These results suggest that the charge on camptothecin can affect the drug's sensitivity to MDR1. The possible effect of membrane permeability in determining drug selectivity of MDR1 is discussed.