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 microM or less, but for
GL331 concentrations of greater than 1 microM, 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.