Embryotoxic effects of SKI 2053R, a new potential anticancer agent, in rats

SKI 2053R, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e] platinum(II), is a newly developed antitumor platinum complex derived from cisplatin. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than cisplatin. The potential of SKI 2053R to induce embryotoxicity was investigated in the Sprague-Dawley rat. One hundred mated rats (sperm in vaginal lavage = Day 0) were distributed among three treated groups and a control group. SKI 2053R was administered intravenously to pregnant rats from Days 6 to 16 of gestation at dose levels of 0, 0.75, 1.5, and 3.0 mg/kg/d. All dams were subjected to caesarean section on Day 20 of gestation. At 3 mg/kg, reduced food intake, reduced body weight, and decreased liver weight were observed in dams. An increase in the resorption rate and a reduction in the fetal weight were also found. In addition, various types of visceral and skeletal malformations occurred at an incidence of 18.5 and 6.0%, respectively. Characteristic malformations included dilated cerebral ventricle, anophthalmia, microphthalmia, fused or absent cervical arch, fused thoracic arch, fused thoracic centrum, and fused rib, among others. Delayed ossification of both sternebrae and metatarsals was also observed. There were no signs of maternal toxicity or embryotoxicity at 0.75 and 1.5 mg/kg. The results show that SKI 2053R is embryotoxic at a minimally maternally toxic dose in rats.