Cell cycle regulation and radiosensitization of TZT-1027, a novel antimicrotubule agent

589 TZT-1027, a dolastatin 10 derivative, is a novel antimicrotubule agent that inhibits tubulin porimerization. TZT-1027 has demonstrated potent antitumor activity against a variety of murine and human tumor cell lines, and effect on cell cycle progression. Since the exact effect on cell cycle progression was not fully understood, we have evaluated cell cycle regulatory mechanism of TZT-1027 using tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. To determine the phase of the cell cycle at which TZT-1027 exert its growth-inhibitory effect, after synchronized at the G2/M phase, tsFT210 cells were treated with different concentrations of TZT-1027 for 6 hours and analyzed by flow cytometry. We have demonstrated TZT-1027 affected on the G2/M phase specifically, leading to G2/M arrest. These data allowed us to examine the possible synergistic effects of TZT-1027 combined with ionizing radiation. A clonogenic assay indicated that H-460 cells were sensitized to gamma radiation by TZT-1027 with 0.2nM concentration using different combining exposure schedules, concurrent and sequential exposure. The DEFs (dose enhancement factors at a surviving fraction of 0.1) were 1.38, 1.61, concurrent exposure schedule, sequential exposure schedule respectively. Currently in vivo investigation with xenograft models is undergoing. Updated results will be presented in the meeting.