Embryo-lethal and teratogenic effect of the new platinum compound DPR in pregnant mice

Embryo-lethal and teratogenic effects caused by the cisplatin-procaine complex cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chlorideplatinum(II) monohydrochloride monohydrate (DPR) were examined in CD-1 mice after a single administration of 7, 14, 21 or 28 mg/kg, injected on day 6, 9, 13 or 16 of pregnancy. At day 18 of pregnancy fetuses were removed and carefully examined for external, visceral and skeletal malformations under a dissecting microscope. A significant reduction of maternal weight gain was observed in pregnant mice after the administration of 21 (day 13) or 28 mg/kg (days 9 and 13) DPR. The exposure to DPR during the organogenesis and early histogenesis periods of prenatal development (administration on day 9 or 13) induced a significant reduction of the mean percentage of live fetuses and a significant increase of the mean percentage of dead and resorbed fetuses. A dose-dependent reduction of fetal body weight was observed in surviving specimens exposed to DPR on embryonic day 9, 13 or 16. The analysis of surviving fetuses killed on day 18 of gestation showed that a few, but statistically significant, external malformations and visceral anomalies were observed after administration of 21 or 28 mg/kg DPR on embryonic day 13. External malformations consisted of three hepato-omphalocele and six palatoschisis (one random palatoschisis was also observed at 21 mg/kg DPR given on day 9), while visceral anomalies included only renal pelvis dilatation. Skeletal anomalies affected fetuses independently of the day of treatment and were more frequent at the highest doses of DPR. They consisted of a delay in skull ossifications, vertebral and sternal anomalies, and formation of extra ribs. A low and non-significant incidence of skeletal malformations (asymmetric sternum) was noticed in fetuses. Our data demonstrated that DPR can cause embryotoxic effects if administered during the period of organogenesis and early histogenesis. Beside embryo-lethality, DPR induced growth retardation and malformations in surviving fetuses.