DEVELOPMENTAL TOXICITY OF GEMCITABINE, AN ANTIMETABOLITE ONCOLYTIC, ADMINISTERED DURING GESTATION TO CD-1 MICE

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, o r 4.5 mg/m2/day, respectively). Animals assigned to the teratology seg ment (25/group) were killed on GD 18 for examination of maternal hemat ologic parameters and organ weights, as well as fetal viability, weigh ts, and morphology. The postnatal segment females (20/group) were allo wed to deliver, and offspring physical, behavioral, and reproductive p arameters were monitored. After offspring weaning, these dams were kil led 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 pa rameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal bo dy weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were consider ed to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live lit ter size in both segments of the study. Additional indications of deve lopmental toxicity in this dose group were an increased incidence of m alformations, primarily cleft palate, decreased fetal weights in the t eratology segment, and decreased neonatal survival in the postnatal se gment. Other indications of offspring toxicity were decreased startle amplitude in the 0.05 and 1.5 mg/kg/day treatment-derived males, and d ecreased ovarian weights in all F1 females compared to controls. Howev er, offspring growth, appearance of physical landmarks, F1 activity le vels, 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 an tiproliferative actions of gemeitabine may be detected at doses below those which result in overt developmental toxicity, i.e., malformation s, weight changes, and decreased prenatal and neonatal survival. (C) 1 993 Wiley-Liss, Inc.