EMBRYOTOXIC EFFECTS OF SKI 2053R, A NEW POTENTIAL ANTICANCER AGENT, IN RATS

SKI 2053B, R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum (II), is a newly developed antitumor platinum complex derived from cis platin, Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than cisplatin, The potential of SKI 2053 R to induce embryotoxicity was investigated in the Sprague-Dawley rat. One hundred mated rats (sperm in vaginal lavage = Day 0) were distrib uted among three treated groups and a control group. SKI 2053R was adm inistered intravenously to pregnant rats from Days 6 to 16 of gestatio n at dose levels of 0, 0.75, 1.5, and 3.0 mg/kg/d, All dams were subje cted to caesarean section on Day 20 of gestation. At 3 mg/kg, reduced food intake, reduced body weight, and decreased liver weight were obse rved in dams, An increase in the resorption rate and a reduction in th e 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 ot hers. 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. (C) 1998 Elsevier Scienc e Inc.