Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle perturbation and apoptosis

Combination of selecting agents that act on different cellular mechanisms i s a common strategy in cancer chemotherapy, GL331 is a new potent topoisome rase II (Topo II) poison; distinctly, paclitaxel is a microtubule-interferi ng cancer chemotherapeutic agent. In this study, we intended to evaluate th e efficacy of combining GL331 with paclitaxel in cell killing and apoptotic induction in nasopharyngeal carcinoma NPC-TW01 cells. By MTT and internucl eosomal DNA cleavage assays, we found that pretreatment or simultaneous tre atment of NPC-TW01 cells with GL331 could significantly interfere with pacl itaxel's cell killing and apoptosis-inducing activity. When the administrat ion schedule was reversed, the cytotoxicity of GL331 was attenuated by pacl itaxel pretreatment. The anti-cancer activity produced by combining GL331 w ith paclitaxel was obviously lower than the addition of the activities of t wo individual agents. NPC-TW01 cells were treated with GL331 and H-3-labele d paclitaxel simultaneously or with GL331 before H-3-labeled paclitaxel. In both conditions, GL331 did not reduce the [H-3]paclitaxel level in the cel ls, suggesting that GL331's interference with paclitaxel's cell-killing and apoptosis-inducing efficacy did not result from any inhibition of cellular uptake or retention of paclitaxel. In addition, we found that GL331-induce d perturbation of cell cycle progression dramatically over-rode the pattern s of mitotic arrest induced by paclitaxel, and the mechanism could be the i nhibition of cyclin B1/CDC2 kinase and MAD2 checkprotein activities. [(C) 2 001 Lippincott Williams & Wilkins].