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 t han its congener VP-16 in killing several types of cancer cells, that has p romoted considerable interest in its possibility of clinical use. In this s tudy, we found that the higher cytotoxicity of GL331 in nasopharyngeal carc inoma NPC-TW01 cells was attributed to the elevated ability to induce apopt otic 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 oc curred upon initial 8-h exposure, and pretreatment of NPC-TW01 cells with G L331 for 8 h significantly interfered with the cytotoxicities of VP-16, cis platin, 5-fluorouracil and adriamycin. When the schedule of drug administra tion was reversed, high-toxic concentrations of these agents revealed an an tagonistic 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 mu M or less, but for GL331 concentrations of greater than 1 mu M, the effect became less than additive. These data suggest that overlapping mecha nisms could be elicited by GL331 and other agents, and additional preclinic al studies are needed to determine the optimal dose combination and adminis tration schedule that will enhance, rather than interfere with, the efficac y of GL331 in combination with other anti-cancer agents.