Cell Cycle Phase-specific Cytotoxicity of the Antitumor Agent Maytansine1

The objective of this investigation was to study the effects of maytansine on the cell cycle kinetics of HeLa cells. The results of this study indicate that maytansine is a very potent mitotic inhibitor and that it has no effect on macromolecular synthesis. Maytansine-induced cytotoxicity was dependent upon the p0sition of the cell in the cell cycle. Mitotic and G2cells are most sensitive to this agent, while G1 phase cells are the most resistant, with S-phase cells being intermediate. Small (0.82 x 10-8 M)fractionated doses given at an interval of 8 hr have been found to be more cytotoxic than was a large (1.64 x 10_a M) single dose. In evaluating the drug combinations, we ob served that the schedule in which I -fJ-D-arabinofunanosylcy tosine treatment was followed by maytansine treatment ex hibited greater cell kill than the reverse sequence. No schedule dependent effects were observed when maytansine was tried in combination with Adniamycin.