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

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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.

Authors

Sooryakumar, Dhriti; Dexheimer, Thomas S; Teicher, Beverly A; Pommier, Yves;

Keywords

  • Antineoplastic Agents/ chemistry
  • Antineoplastic Agents/ metabolism
  • Antineoplastic Agents/ pharmacology
  • Base Sequence
  • Camptothecin/ pharmacology
  • Cell Line, Tumor
  • DNA Topoisomerases, Type I/ metabolism
  • Drug Resistance, Neoplasm/ drug effects
  • HCT116 Cells
  • Histones/ metabolism
  • Humans
  • Naphthyridines/ chemistry
  • Naphthyridines/ metabolism
  • Naphthyridines/ pharmacology
  • Neoplasms/ metabolism
  • Neoplasms/ pathology
  • Topoisomerase I Inhibitors/ chemistry
  • Topoisomerase I Inhibitors/ metabolism
  • Topoisomerase I Inhibitors/ pharmacology

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