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, or 4.5 mg/m2/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Eudaly
J A
JA
Toxicology Research Laboratories, Division of Eli Lilly & Company, Greenfield, Indiana 46140.
Tizzano
J P
JP
Higdon
G L
GL
Todd
G C
GC
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced*; D005865:Gestational Age; D006410:Hematopoiesis / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D012098:Reproduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine