Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.

Journal Article (Journal Article)

BACKGROUND: Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development. PROCEDURES: Genz-644282 was tested against the PPTP in vitro panel (0.1 nM to 1 µM), and in vivo using three times per week × 2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4 mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1 mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively. RESULTS: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM). In vivo, Genz-644282 at its MTD (4 mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2 mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1 mg/kg. Further testing at 2 mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282. CONCLUSIONS: Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent.

Full Text

Duke Authors

Cited Authors

  • Houghton, PJ; Lock, R; Carol, H; Morton, CL; Gorlick, R; Anders Kolb, E; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, CA; Zhang, MX; Madden, SL; Teicher, BA; Smith, MA

Published Date

  • February 2012

Published In

Volume / Issue

  • 58 / 2

Start / End Page

  • 200 - 209

PubMed ID

  • 21548007

Pubmed Central ID

  • PMC3154998

Electronic International Standard Serial Number (EISSN)

  • 1545-5017

Digital Object Identifier (DOI)

  • 10.1002/pbc.23016


  • eng

Conference Location

  • United States