Embryotoxicity of 5-azacytidine in mice. Phase- and dose-specificity studies.

The agent 5-azacytidine, which directly affects nucleic acid metabolism, is a potent teratogen in NMRI mice. The establishment of general teratological data revealed clear-cut dose-response relationships after administration of this agent on either day 12 or day 14 of gestation. Inspection of skeletal abnormalities revealed a clear-cut phase specificity of this drug when administered on days 10 or 11 of pregnancy. Additional histological studies showed that central nervous system anomalies were induced mainly after administration of azacytidine on days 10, 11, 12, or 13 of pregnancy. A most conspicuous finding was the formation of anomalous glioblast islets within the ventricular zone covering the basal ganglia. The latter malformation mainly occurred after treatment on day 11 or 12 of pregnancy. Another important malformation syndrome was the appearance of capillary ectasias and hind paw hematomas, together with an intense necrotic cardiomyopathy after treatment on either day 11 or 12 of gestation.