Genz-644282

Description: IC50 Value: 1.2 nM [1] Genz-644282 [8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one] has emerged as a promising candidate of non-Camptothecin topoisomerase I inhibitor for antitumor agents. in vitro: Genz-644282 demonstrated potent cytotoxic activity with a median IC(50) of 1.2 nM (range 0.2-21.9 nM) [1]. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR [3]. 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 [1]. Genz-644282 was tolerated at doses up to 4 mg/kg when administered intravenously on alternate days, and the compound was active at doses from 1 to 4 mg/kg. The efficacy of Genz-644282 was compared with irinotecan in 4 human colon carcinoma xenograft models. In the human HCT-116 colon cancer xenograft, TGD values were 14 days for irinotecan (60 mg/kg) and 34 days for Genz-644282 (2.7 mg/kg), giving maximum test to control ratios (T/Cs) of 23.7% and 16.8%, respectively [2]. Clinical trial: Dose-Escalation Study to Assess the Safety and Tolerability of Genz-644282 in Patients With Solid Tumors. Phase 1