Genz-644282 is a cytotoxic agent and shows activity in several human tumor cell lines. 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. Genz-644282 was highly active within a narrow dose range (2-4 mg/kg), typical of other topoisomerase I poisons. Genz-644282 has superior or equal antitumor activity in the human tumor xenografts than the standard compound comparators.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282.
Sooryakumar D, et al. Mol Cancer Ther. 2011 Aug;10(8):1490-9. PMID: 21636699.
Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program.
Houghton PJ, et al. Pediatr Blood Cancer. 2012 Feb;58(2):200-9. PMID: 21548007.
Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment.
Kurtzberg LS, et al. Clin Cancer Res. 2011 May 1;17(9):2777-87. PMID: 21415217.
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