Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD‐1 mice

Abstract

Abstract Gemcitabine was given intravenously to female mice on gestation days (GD) 6–15 at doses of 0, 0.05, 0.25, or 1.5 mg/kg/day (0, 0.15, 0.75, or 4.5 mg/m 2 /day, respectively). Animals assigned to the teratology segment (25/group) were killed on GD 18 for examination of maternal hematologic parameters and organ weights, as well as fetal viability, weights, and morphology. The postnatal segment females (20/group) were allowed to deliver, and offspring physical, behavioral, and reproductive parameters were monitored. After offspring weaning, these dams were killed for hematologic and organ weight evaluations. At necropsy, 3 days after the final dose, the teratology segment dams showed dose‐related increases in spleen and thymus weights. These changes were accompanied by a dose‐related decrease in leukocytes and modest increases in mean corpuscular volume (MCV) and hemoglobin (MCH) at the two higher doses. On postpartum day (PPD) 21, the dams in the postnatal segment showed no treatment‐related effects on these organ weights or hematologic parameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal body weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were considered to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live litter size in both segments of the study. Additional indications of developmental toxicity in this dose group were an increased incidence of malformations, primarily cleft palate, decreased fetal weights in the teratology segment, and decreased neonatal survival in the postnatal segment. Other indications of offspring toxicity were decreased startle amplitude in the 0.05 and 1.5 mg/kg/day treatment‐derived males, and decreased ovarian weights in all F 1 females compared to controls. However, offspring growth, appearance of physical landmarks, F 1 activity levels, active and passive avoidance, and reproductive performance were not affected adversely in the surviving offspring of the 1.5 mg/kg/day treatment‐derived group or in mice from either of the two lower dose groups. These results indicate that maternal effects related to the antiproliferative actions of gemcitabine may be detected at doses below those which result in overt developmental toxicity, i.e., malformations, weight changes, and decreased prenatal and neonatal survival. © 1993 Wiley‐Liss, Inc.