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Clinically relevant resistance to the currently approved camptothecins, irinotecan and topotecan, is poorly understood but may involve increased expression of ATP-dependent drug transporters such as ABCG2 (BCRP). Gimatecan is a lipophilic 7-substituted camptothecin derivative that exhibits potent anti-tumor activity in a variety of preclinical cancer models and is under investigation in the clinic. Previous studies reported that gimatecan cytotoxicity was not affected by expression of ABCG2. To confirm and extend this finding, we assessed the cytotoxicity of gimatecan in pairs of isogenic cell lines consisting of transfectants expressing either ABCG2 (including wild-type or R482T or R482G mutants), ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2), or ABCC4 (MRP4). Expression of ABCG2 or mutants in HEK293 cells conferred resistance to topotecan but not to gimatecan. Similarly, intracellular accumulation of gimatecan was unaffected by expression of wild-type or mutant ABCG2. Furthermore, expression of ABCB1 or ABCC2 did not alter gimatecan cytotoxicity. By contrast, over expression of either ABCC1 or ABCC4 reduced the anti-proliferative effects of gimatecan. In particular, over expression of ABCC4 conferred a high-level (3-log increase in IC50) of resistance to gimatecan. Additionally cells containing point mutations in topoisomerase I, conferring resistance to topotecan and irinotecan, were also resistant to gimatecan. These results suggest that gimatecan may be more effective than irinotecan or topotecan in cancers that express ABCG2, ABCB1 or ABCC2 but not in cancers that express ABCC4, or contain certain TOP1 mutations.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA