ABSTRACT
Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPR-derived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin-derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13-18 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC(0.5-24)= 3.40 vs. 4.95 microg.h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC0.13-2h s of 7.5 and 6.6 microg.h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08+/-0.30 vs. 0.78 +/- 0.35 microg/g, p <0.10), an opposite situation was found in the kidney (0.51+/-0.20 vs. 0.69 +/- 0.22 microg/g, p <0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin.
Subject(s)
Abnormalities, Drug-Induced/metabolism , Cisplatin/analogs & derivatives , Cisplatin/pharmacokinetics , Embryo, Mammalian/metabolism , Fetus/metabolism , Organoplatinum Compounds/pharmacokinetics , Platinum/metabolism , Procaine/analogs & derivatives , Procaine/pharmacokinetics , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Cisplatin/administration & dosage , Cisplatin/toxicity , Embryo, Mammalian/drug effects , Female , Fetal Weight/drug effects , Fetus/drug effects , Gestational Age , Injections, Intraperitoneal , Male , Mice , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/toxicity , Platinum/analysis , Pregnancy , Procaine/administration & dosage , Procaine/toxicity , Spectrophotometry, Atomic/methodsABSTRACT
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.
