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

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 cell

SUBMITTER: Sooryakumar D 

PROVIDER: S-EPMC3155218 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature