Teratogenic and cytogenetic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice

Abstract

The teratogenic effects of three new plant-derived antitumor agents, maytansine, VP-16-213 and VM-26, were compared to the effects of vincristine and colchicine in pregnant Swiss albino mice that received a single ip injection of drug on day 6, 7 or 8 of gestation. Cytogenetic studies were also performed using maternal bone marrow and embryos obtained 48 hours after injection of maytansine, vincristine, VP-16-213, VM-26 and colchicine on day 6, 7 or 8 of gestation. A close correlation between teratogenic and cytogenetic effects was not noted among the compounds tested. Vincristine had greater embryotoxic and teratogenic activity than maytansine at equimolar doses (0.36 mu moles/kg), with the peak effects appearing after injection on day 7 of gestation. Colchicine, VP-16-213 and VM-26 were comparatively less potent than maytansine and vincristine, since doses of 2.5 mu moles/kg (colchicine and VP-16-213) and 1.5 mu moles/kg (VM-26) were required to elicit embryotoxic effects. At their teratogenic doses, all compounds induced various cranial abnormalities including exencephaly, hydrocephalus, anophthalmia and microtia, as well as major skeletal malformations. The teratogenic dose of vincristine is comparable to its effective antitumor dose in transplantable rodent tumor systems; in contrast, the teratogenic dose of maytansine in approximately 10-fold higher than its antitumor dose. Of the compounds studied, VP-16-213 and VM-26 exerted the most consistent cytogenetic effects in embryonic tissue. Alarge proportion of the structural chromosome aberrations induced in embryonic cells by VM-26 were stable and are most likely capable of surviving at least one cell division.