Embryotoxicity in mice of phosphonacetyl-L-aspartic acid (PALA), a new antitumor agent. II. Studies on its mechanism and reversibility.

The embryolethal effects of phosphonacetyl-L-aspartic acid (PALA) are markedly gestational stage-specific in the Swiss albino mouse. Embryos are most sensitive to the lethal effects of PALA on days 7 and 8 of gestation, with embryonic LD50's of 9 and 8 mg/kg, respectively. In contrast, the embryonic LD50 on day 10 of gestation is 144 mg/kg. Following an IP dose of (acetyl-14C)-PALA to pregnant mice, approximately threefold higher levels of radioactivity were present in day 8 than in day 10 embryonic tissue, whereas the radioactive content of placentas from day 10 pregnant animals was significantly higher than in placentas from day 8 pregnant mice. Similarly, L-aspartate transcarbamylase (ATCase) activity was greater in maternal spleen, placentas, and embryos on day 8 than on day 10 of gestation, and PALA treatment produced a greater inhibition of ATCase in embryonic tissue on day 8 than on day 10; however, inhibition of placental ATCase activity was more pronounced on day 10 than on day 8. Neither single nor multiple doses of uridine (UR) given orally to pregnant mice on day 8 of gestation were effective in reducing day 8 PALA embryolethality. Carbamyl-L-aspartic acid, given in the drinking water of pregnant mice on days 7-9 of gestation, reduced the day 8 embryolethality of PALA from 100% to approximately 50%. In a similar experiment, the presence of UR in the drinking water of pregnant mice reduced PALA-induced embryolethality in day 10, but not day 8, embryos. These results indicate that the embryotoxic effects of PALA are the result of ATCase inhibition; furthermore, they suggest that the relative insensitivity of the day 10 embryo to the lethal effects of PALA may result either from a greater availability of UR to the day 10 (versus the day 8) embryo, or from an enhanced ability of the day 10 placenta to bind PALA and prevent its passage into the embryo.