Abstract C220: Genz-644282, a non-camptothecin topoisomerase one inhibitor, demonstrates a wide spectrum of in vitro and in vivo antitumor activity

Abstract Genz-644282 (GZ) is a novel non-camptothecin topoisomerase I (Top1) inhibitor. The in vitro and in vivo activity of GZ and its M1 and M2 metabolites were explored and compared with the activity of camptothecin Top1 inhibitors. In vitro in mouse, rat, dog, and human GZ exhibited high metabolic stability, plasma binding of 88–93% and exhibits concentration dependent partitioning into red blood cells. In vivo, GZ has a large volume of distribution and low-to-moderate clearance in mouse, rat and dog. In nude mice, the t1/2 for GZ is 3.6 h (po), 10.4 h (ip) and 5.1h (iv) and longer in tumor-bearing mice. In human HCT-116 colon ca, HT-29 colon ca and NCI-H460 NSCLC cells the concentration response for Genz-6244282, M1 and M2 are the same. Upon 72h exposure of the cells to GZ, M1 or M2 the IC50 concentrations were 0.5-0.65 nM and the IC90 concentrations were 1.8–2 nM. In order to evaluate the antitumor activity of GZ as compared to several approved anticancer agents, the compound was tested in seven xenograft models: LOX-IMVI melanoma, DLD-1 and HCT-15 colon, MDA-MB-231 breast, NCI-H292 and NCI-H1299 lung ca. GZ was compared against two of its metabolites, Genz-649974 (GZ-74) and Genz-649975 in the HCT-116 colon ca resulting in comparable activity with GZ-74. GZ was administered intravenously on a QODx3 schedule for 2 cycles. The tumor growth delay, TGD, (T-C) and increase in lifespan, ILS, (T/C) for each study are listed in the table below. All of the GZ dosages were well tolerated resulting in a maximum body weight loss of ≤20%, except for the high dosages in the HCT-15 and NCI-H292 in which there was a maximum body weight loss of 25.7 and 20.9%, respectively. Based on these findings and other data, GZ was selected to be a development candidate. Treatments Dose (mg/kg/day) Route/Schedule TGD (T-C) ILS (T/C) Tumor Line GZ 1 IV/QODx3 2 days 1.1x for 2 cycles GZ 4 IV/QODx3 25 days 2.8x LOX-IMVI Dacarbazine 90 IP/QDx5 14 days 2.0x GZ 4 IV/QODx3 8 days 1.2x for 2 cycles CPT-11 60 IV/Q4Dx3 5 days 1.1x DLD-1 for 2 cycles GZ 1 IV/QODx3 14 days 1.3x for 2 cycles GZ 2 IV/QODx3 35 days 1.8x HCT-15 for 2 cycles CPT-11 60 IV/Q4Dx3 28 days 1.7x GZ 1 IV/QODx3 21 days 1.7x for 2 cycles GZ 1.36 IV/QODx3 >47 days >2.3x MDA-MB-231 for 2 cycles GZ 1.7 IV/QODx3 35 days 2.0x for 2 cycles Docetaxel 20 IV/QODx3 >47 days >2.3x GZ 1 IV/QODx3 18 days 1.5x for 2 cycles GZ 1.36 IV/QODx3 21 days 1.6x for 2 cycles NCI-H292 GZ 1.7 IV/QODx3 21 days 1.6x for 2 cycles Docetaxel 20 IV/QODx3 39 days 2.1x GZ 1 IV/QODx3 20 days 1.7x for 2 cycles GZ 1.36 IV/QODx3 24 days 1.8x for 2 cycles NCI-H1299 GZ 1.7 IV/QODx3 34 days 2.1x for 2 cycles Docetaxel 20 IV/QODx3 17 days 1.6x GZ-74 4 IV/QODx3 25 days 1.8x for 2 cycles GZ-74 6 IV/QODx3 28 days 1.9x for 2 cycles HCT-116 GZ-74 8 IV/QODx3 32 days 2.0x for 2 cycles GZ 1.7 IV/QODx3 28 days 1.9x for 2 cycles Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C220.