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

ABSTRACT:

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

SUBMITTER: Houghton PJ 

PROVIDER: S-EPMC3154998 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature