Hematologic and histopathologic evaluation of N-(phosphonacetyl)-l-aspartate (PALA) in mice

Summary The study reported here was designed to provide a preliminary indication of the qualitative and quantitative toxicity of N-(phosphonacetyl)-l-aspartate (PALA). PALA was administered IP to male B6D2F1 mice (22–24 g) daily for 9 days in dosages of 180, 220, and 290 mg/kg. These dosages were chosen to approximate 0.8 LD₁₀, LD₁₀, and LD₅₀, based on historical 30-day lethality data. Five mice from each dosage group were killed on days 6, 10, 16, and 30 (day of first treatment = day 1) for hematologic and histopathologic evaluation. Only minimal changes were detected in peripheral hematologic values. PALA produced reticulocytopenia with a nadir on day 10(24 h after last treatment). Reticulocyte counts were only marginally reduced by 180 mg/kg/day; nadirs were 33% and 23% of control following 220 and 290 mg/kg/day. Lymphopenia was observed on day 10, but it was not as severe in survivors of 290 mg/kg as it was in recipients of the lower dosages. Thrombocytopenia was not observed, and total marrow cell counts did not reflect hematotoxicity. Peripheral hematology was normal in survivors of 180 and 220 mg/kg/day by day 16. Reticulocytopenia in survivors of 290 mg/kg/day persisted, however, and no survivors of this dosage were available for assessment of recovery on day 30. Mild, diffuse hypertrophy of the gastrointestinal epithelium was the most consistent lesion observed. These lesions were most evident on day 10, and they were comparable in severity across the dosage range studied. The mice treated with 180 mg/kg/day exhibited no evidence of gastrointestinal toxicity on day 16; survivors of 220 and 290 mg/kg/day had residual lesions that generally were less severe than on day 10, although the effects of 290 mg/kg were more distinct. No survivors exhibited lesions on day 30. These results suggest that gastrointestinal toxicity may be dose-limiting, but, unlike most other anticancer drugs of the antimetabolite class, PALA may be only mildly hematotoxic.