Effect of edotecarin on cell cycle progression and apoptosis induction in HCT-116 human colon carcinoma model.

Proc Amer Assoc Cancer Res, Volume 45, 2004 3821 Edotecarin is an indolocarbazole derivative, more potent than camptothecin in inhibiting topoisomerase I, active in a panel of in vitro and in vivo human tumor models (Yoshinari et al, Cancer Res. 1999; Arakawa et al, Jpn. J. Cancer Res. 1999). The effect of edotecarin on cell cycle progression and apoptosis induction was studied on HCT-116 human colon carcinoma cells in comparison with SN-38, the active metabolite of irinotecan. Edotecarin and SN-38 produced very similar cell cycle perturbations as both of them initially blocked the cells in S phase, followed by an accumulation in G2: a 3 fold increase in the late S phase was observed after 14-h treatment with 10 nM of both compounds. This observation was also confirmed ex vivo in tumors from mice treated with edotecarin and irinotecan. The cell cycle block had a longer duration in the edotecarin-treated than in the SN-38-treated cells: the effect of 1-h treatment with 300 nM of edotecarin or SN-38 was maintained for 72 h and 24 h, respectively. Moreover, whereas SN-38 was mainly affecting the cells that were synthesizing DNA, edotecarin hit all the cells, independently from the cell cycle phase. Finally, edotecarin was as potent as SN-38 in inducing cell apoptosis after a 24-h treatment (300 nM of both compounds produced c 30 % of apoptotic cells), but it was more potent than SN-38 with a 6-h treatment (17% vs 5% of apoptotic cells respectively).