Ja. Eudaly et al., DEVELOPMENTAL TOXICITY OF GEMCITABINE, AN ANTIMETABOLITE ONCOLYTIC, ADMINISTERED DURING GESTATION TO CD-1 MICE, Teratology, 48(4), 1993, pp. 365-381
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.