Uses
GENZ-644282 is used in the synthesis of ARC-111 analogs in the improvement of the antitumor activity of the parent compound.
Uses
GENZ-644282 is used in the synthesis of ARC-111 analogs in the improvement of the antitumor activity of the parent compound.
Biological Activity
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].
