Teratogenesis and inhibition of DNA synthesis induced in rat embryos by cytosine arabinoside.

Pregnant Wistar rats were injected at day 12 of gestation with 25, 50, 100, or 200 mg/kg cytosine arabinoside. One to 27 hours later 3H-thymidine was also injected followed 2 hours later by surgical removal of one uterine horn. The remaining horn was left in situ until day 20 for evaluation of embryotoxicity (malformation, death, or growth retardation). Half of the embryos in the removed horn were prepared individually for whole-embryo scintillation counts and the other half were homogenized and treated with perchloric acid, of which the acid-insoluble fraction was quantitated for 3H-thymidine incorporation by scintillation counting. Other pregnant rats were treated with cytosine arabinoside and allowed to continue to day 20 without further treatment. Twenty-day fetuses from females given cytosine arabinoside at day 12 showed dose related malformation and growth retardation but not death following 50 to 200 mg/kg. These effects were more severe when treatment was followed by thymidine injection and partial hysterectomy. The latter procedures revealed striking and dose related suppression of DNA synthesis evidenced by 3H-thymidine incorporation 1 to 27 hours after cytosine-arabinoside injection. Embryotoxic effects in 20-day fetuses were more closely related to the cumulative suppression of DNA synthesis caused by a given dosage than with either the level at any one posttreatment interval or the duration of the suppression. Although all dosages caused reduction in the rate of DNA synthesis to less than 25% of control rate 1 hour following treatment, after the smaller dosages recovery to control rate occurred by 15 hours whereas after 200 mg/kg recovery was not complete even after 27 hours. Surprisingly, 12-day rat embryos exhibited suppression of DNA synthesis of between 25 and 75% of control rate for up to 9 hours with little effect being apparent in 20-day fetuses.