Phase II evaluation of N-(phosphonacetyl)-L-aspartic acid (PALA) in patients with non-small cell carcinoma of the lung

Asparate transcarbamylase catalyzes a key reaction in the pathway of pyrimidine biosynthesis, the condensation of carbamyl phosphate with aspartic acid, generating carbamyl-L-aspartate. N-(Phosphonacetyl)-L-aspartic acid (PALA), a stable analog of the transition state in that reaction, is a potent inhibitor of asparate transcarbamylase. PALA has demonstrateed antitumor activity in both Lewis lung carcinoma and B16 melanoma, two solid tumor models resistant to other antimetabolites. Phase I studies have shown that PALA given at a weekly dose of 4.5 g/m ² is nonmyelosuppressive and produces moderate, but manageable, gastrointestinal and cutaneous toxicity. Most of the drug is excreted unmetabolized in the urine. Because of its unique site of action, its activity in resistant solid tumor models, and its lack of myelotoxicity, a phase II study of PALA in non-small cell lung cancer was initiated.