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

Peter J. Houghton, Richard Lock, Hernan Carol, Christopher L. Morton, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, John M. Maris, Catherine A. Billups, Mindy X. Zhang, Stephen L. Madden, Beverly A. Teicher, Malcolm A. Smith

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 (0.1nM to 1μM), and in vivo using three times per week×2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1mg/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 1.2nM (range 0.2-21.9nM). In vivo, Genz-644282 at its MTD (4mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1mg/kg. Further testing at 2mg/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 (2-4mg/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.

Original languageEnglish (US)
Pages (from-to)200-209
Number of pages10
JournalPediatric Blood and Cancer
Issue number2
StatePublished - Feb 2012
Externally publishedYes


  • Developmental therapeutics
  • Genz-644282
  • Preclinical testing

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Pediatrics, Perinatology, and Child Health


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