Different teratogenic efficacy to mouse fetal CNS of 5-azacytidine in combination with X-irradiation depends on the sequence of successive application.

The single treatment of pregnant mice on day 12 post conception with 5-azacytidine (AzaCr), followed by a single irradiation dose of 200 rad two hours later, is exclusively neurotoxic to the fetus, as shown by a severe hypoplasia of the parieto-occipital regions of the telencephalon. This effect is explicable by the specific function of the mitotic cell population for the integrity of the cortex wall. Combining these two hazards in the reverse manner, i.e., irradiation followed by AzaCr, resulted in no general hypoplastic effect in the forebrain and only caused a depletion of cells in the marginal cortex. This indicates a significantly diminished AzaCr sensitivity of fetal cortical cells subsequent to X-irradiation. In addition, rosette-like cell clustering in the cortex of all X-irradiated animals occurs to a similar degree, irrespective of any additional AzaCr-treatment. The only conformity between these different schedules is that a great portion of the surviving cells is most likely in the DNA synthesizing phase at the time of irradiation. It is therefore concluded that rosette formation starts perferentially from cells injured during the S-phase.