Abstract
Abstract Camptothecin (CPT) derivatives are powerful anticancer drugs because of their ability to trap topoisomerase I (Top1)-DNA cleavage complexes. However, they exhibit clinical limitations due to the instability of their α-hydroxylactone six-membered E-ring structure, which is essential for trapping Top1-DNA cleavage complexes. Additionally, they exhibit bone marrow and intestinal toxicity in adults and are drug efflux substrates. Here, we report a Top1 inhibitor, Genz644282. In the cell lines studied, we find that Genz644282 as well as its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with CPT. The compound also induces protein-linked DNA breaks and Top1-DNA cleavage complexes that persist longer after drug removal than CPT. Concentration-dependent and persistent H2AX formation was readily observed in cells treated with Genz644282, and was present in greater than 50% of the cell population following 24 hours drug treatment. The compound shows partial cross-resistance in cell lines resistant to CPT. These cell lines include the prostate cancer cell line (DU145RC0.1), and human leukemic (CEM/C2) cells. Genz644282 demonstrated limited cross-resistance in Top1-knockdown colon cancer (HCT116) and breast cancer (MCF7) cells. The compound also demonstrated limited resistance in human lung cancer cells (H460/MX20). These lung cancer cells express (BCRP, ABCG2), a member of the ATP-binding cassette family of cell surface transport proteins known to have ABCG2 drug-efflux pumps. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C219.
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