TERATOGENIC EFFECT OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN RAT - PROTECTION BY DEOXYCYTIDINE

Single i.p. injections of 1-β-D-arabinofuranosylcytosine (ara-C) at doses ranging from 20-800 mg/kg of body wt. given to the pregnant Wistar rat from day 10-12 of gestation produced malformations which included cleft palate and lip, encephalocele, and deformed appendages and tail in fetuses that survived to day 21 of gestation. No malformations were observed in fetuses at 21 days with any of the doses (5-500 mg/kg) given to the pregnant rat on day 5-9 of gestation. The effectiveness of 1-β-D-2'-deoxy-ribofuranosylcytosine (CdR) in preventing fetal malformations at 21 days, produced by a single i.p. injection of 150 mg/kg or ara-C given to the 12-day-pregnant rat was dependent on the amount of CdR and of intervals of time between the administration of the two compounds. If the time interval between administration of ara-C (150 mg/kg) and CdR (600 mg/kg) exceeded 10 min, complete protection against ara-C-induced malformations did not occur. 1-β-D-deoxyribofuranosyl-5'-phosphate (dCMP) gave protection in the same range as CdR, but 1-β-D-ribofuranosylcytosine-5'-phosphate (CMP), 1-β-D-ribofuranosylcytosine diphosphate (CDP), 1-β-D-ribofuranosylcytosine (CR) and thymidine (TdR) did not. When tritium-labeled ara-C (282.5 mg/kg) was given i.v. to the 12-day-pregnant rat, about 30 per cent of the injected dose was excreted in the urine within 24 hr, with only minor amounts being deaminated to 1-β-D-ribofuranosyluracil (ara-U); fetuses from these rats extracted 1-2 hr after injection showed about 97.5 per cent of the radioactivity in the trichloracetic acid (TCA), 2.5 per cent in the DNA, and no activity in the RNA and protein fractions. © 1968.