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Mol Cancer Ther. 2011 Aug;10(8):1490-9. doi: 10.1158/1535-7163.MCT-10-1043. Epub 2011 Jun 2.

Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282.

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  • 1Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.

Abstract

Camptothecin 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. In addition, they exhibit bone marrow and intestinal toxicity, especially in adults, and are drug efflux substrates. Here, we report a novel Top1 inhibitor, Genz-644282. We show that Genz-644282 and its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with camptothecin. The compound also induces protein-linked DNA breaks and Top1-DNA cleavage complexes that persist longer after compound removal than camptothecin. Concentration-dependent and persistent γH2AX formation was readily observed in cells treated with Genz-644282, and was present in greater than 50% of the cell population following 24 hours compound exposure. The compound shows partial cross-resistance in cell lines resistant to camptothecin. These cell lines include the human prostate DU145RC0.1 and the leukemic CEM/C2 cells. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR. Together, our results provide the first molecular and cellular characterization of Genz-644282 and its clinically relevant metabolites.

©2011 AACR

PMID:
21636699
[PubMed - indexed for MEDLINE]
PMCID:
PMC3155218
Free PMC Article
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