Developmental toxicity of the topoisomerase inhibitor, etoposide, in rabbits after intravenous administration.

Abstract

The developmental effect of the topoisomerase inhibitor, etoposide, was investigated in pregnant rabbits given intravenous doses during early organogenesis. Does received 0, 0.25, 0.5, 1, or 2 mg/kg/day on days 7 through 9 of gestation. Fetal parameters were evaluated on day 28 of gestation. Live fetuses were examined for gross, visceral, and skeletal malformations and variations. In addition, telencephalon in embryos 8 h following the final treatment was examined histologically. No change in general condition was observed in any does, but a significant decrease in body weight gain during the pregnancy and enlargement of the liver resulting from marked fatty change were observed in does treated with etoposide at 2 mg/kg/day. Etoposide had neither lethal nor growth retarded effects on embryos/fetuses. However, axial skeletal malformation and extra ribs had a low incidence but were significant in the group treated with etoposide at 2 mg/kg/day, whereas no significant increases in external malformations in term fetuses nor in pyknotic cells in the ventricular zone of telencephalon in embryos were noticed in any etoposide-treated groups. It was concluded that anatomical defects (skeletal malformation or variation) in rabbits were induced by intravenous etoposide treatment during early organogenesis and that they occurred in the presence of maternal toxicity.