Protective effect of deoxycytidylic acid (CdMP) on hydroxyurea-induced malformations in rats.

Abstract

AbstractSingle ip injections of 500 mg/kg hydroxyurea (HU) to 11‐day pregnant rats produced minimal fetal mortality and malformations of the limbs, palate, jaw, and tail in 98.8% of fetuses surviving to day 21 of gestation. Simultaneous administration of 500 mg/kg HU and 700 mg/kg deoxycytidylic acid (CdMP) provided complete protection against HU teratogenesis. Lower doses of CdMP (3.7–500 mg/kg) gave partial, dose‐related, protection, as indicated by increased frequency of normal survivors and decreased severity of specific malformations. Maximal protection was provided to the forepaw and jaw and minimal to the tail. In experiments in which 700 mg/kg CdMP were given 15–60 minutes after or up to 150 minutes before HU administration, its protective effect gradually diminished with lengthening of time between the administration of the two compounds. The incidence and manifestation of individual malformations in both sets of experiments were time related. When a mixture of 700 mg/kg of CdMP and 500 mg/kg of HU was left at room temperature for 15 minutes before injection, the protective effect of CdMP was diminished by 15.1%. When the effects of several pyrimidine compounds were equated on the basis of biochemically equivalent doses (mmol/kg), among the cytidine derivatives CdMP was more effective at all doses than cytidine or deoxycytidine. All cytidine compounds gave greater protection than the uridine compounds, whereas thymidine and thymidylic acid did not protect the fetal rat against HU‐induced malformations.