Embryotoxicity in mice of phosphonacetyl-L-aspartic acid (PALA), a new antitumor agent. I. Embryolethal, teratogenic, and cytogenetic effects.

The embryolethal and teratogenic effects of phosphonacetyl-L-aspartic acid (PALA), a new antitumor agent, were evaluated in pregnant Swiss albino mice that received multiple IP injections of drug on days 7-11 of gestation. The effects of single doses of PALA given IP on days 4, 5, 6, 7, 8, 9, or 10 of gestation were also examined. Cytogenetic studies were performed on cells from embryos exposed in utero to embryotoxic doses of PALA, as well as on human peripheral leucocytes incubated with PALA for six or 48 hours. When given on days 7-11 of gestation, marked embryolethal effects were noted at PALA doses of 1.5 mg/kg/day, and no embryos survived doses of 6.25 mg/kg/day. Studies on the effects of PALA administered as a single dose on various days of gestation revealed that its embryolethal effects were gestation stage-specific; 80% of embryos were killed in utero after exposure to a dose of 12.5 mg/kg on day 8, whereas doses nearly 20-fold higher (200 mg/kg) were required to exert equivalent embryolethal effects on day 6 or 10 of gestation. PALA treatment induced an increase primarily in the incidence of malformations which occur spontaneously in control mice rather than in malformations not normally seen in controls. PALA embryotoxicity in mice apparently does not derive from major cytogenetic damage, as the incidence of chromosomal aberrations was not significantly increased by in vitro or in vivo exposure to PALA.