Pre-clinical studies of a novel anti-mitotic agent, amphethinile.

Abstract

A new antitumour agent is described, which has been shown to induce a G2/M block in murine leukaemia cells in vitro. In addition this agent has been shown to be equally toxic toward parental and daunorubicin-resistant P388 cells in vitro. These resistant cells are highly cross-resistant to the established anti-mitotic agents vincristine and vinblastine. Drug accumulation studies in cells have shown that whereas resistance in this cell line is associated with decreased drug accumulation in the case of daunorubicin, vincristine and vinblastine, this effect is much less pronounced for amphethinile. It is proposed that amphethinile is a poor substrate for the drug efflux process associated with the pleiotropic resistance mechanism operating in these cells. The data suggest that cell sensitivity towards amphethinile differs qualitatively from that of the vinca alkaloids and anthracycline. Pharmacokinetic studies in male mice were undertaken. Area under the curve values (AUC), show that levels of approximately 313 micrograms l-1 h-1 were attained at doses equivalent to the LD10. The alpha half life is approximately 8 min after a bolus intravenous injection. The beta half life was approximately 100 min and relatively independent of dose level.