Reproduction studies of VP 16-213 (V)--Intravenous administration to rats prior to and in the early stages of pregnancy

Abstract

VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to male Crj: CD (Sprague-Dawley) rats for 61 days and to female rats of the same strain for 14 days prior to mating at dose levels of 0.05, 0.2 and 0.8 mg/kg/day. These animals were then mated under the consecutive administration of this drug and the females confirmed to be copulated were further dosed from day 0 through 7 of gestation. The summarized results obtained are as follows: Body weight increases were suppressed at the dose level of VP 0.8 mg/kg in males and females. VP 0.2 and 0.8 mg/kg decreased the thymic weight and 0.8 mg/kg decreased testicular and epididymal weight in males showing macroscopic atrophy of these organs, but these doses failed to affect the reproductive ability and so on in parent rats. As for fetuses, VP 0.8 mg/kg elevated the mortality, decreased the number of survivors and suppressed their growth. Furthermore, this dose raised the incidences of anophthalmia, microphthalmia, dilated lateral ventricles and unossified 5th and 6th sternums, as well as brought retarded ossification of sternums, cervical vertebrae, sacral and coccygeal vertebrae, metacarpus and thoracic vertebrae. Based on these results, the no-effect dose levels of VP under the present experimental condition were estimated to be 0.05 mg/kg/day against parent rats of both sexes and 0.2 mg/kg/day against their offspring.