In vitro evaluation of GL331's cancer cell killing and apoptosis- inducing activity in combination with other chemotherapeutic agents

GL331 is a novel podophyllotoxin-derived compound and is more efficacious than its congener VP-16 in killing several types of cancer cells, that has promoted considerable interest in its possibility of clinical use. In this study, we found that the higher cytotoxicity of GL331 in nasopharyngeal carcinoma NPC-TW01 cells was attributed to the elevated ability to induce apoptotic cell death. In addition to evaluation of GL331's single agent activity, the use of GL331 in combination with other established therapeutic agents was also evaluated. We found that GL331-induced cell cycle perturbation occurred upon initial 8-h exposure, and pretreatment of NPC-TW01 cells with GL331 for 8 h significantly interfered with the cytotoxicities of VP-16, cisplatin, 5-fluorouracil and adriamycin. When the schedule of drug administration was reversed, high-toxic concentrations of these agents revealed an antagonistic effect on GL331; however, their low-toxic doses had the additive or even more-than-additive effect on the cytotoxicity induced by GL331 at 0.1 μM or less, but for GL331 concentrations of greater than 1 μM, the effect became less than additive. These data suggest that overlapping mechanisms could be elicited by GL331 and other agents, and additional preclinical studies are needed to determine the optimal dose combination and administration schedule that will enhance, rather than interfere with, the efficacy of GL331 in combination with other anti-cancer agents.