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A Phase I study of the combination N‐(phosphonacetyl)‐L‐aspartate (PALA, NSC‐224131) and L‐alanosine (NSC‐153353) in patients with advanced cancer

This article reports a Phase I study of combined therapy with N‐(phosphonacetyl)‐L‐aspartate (PALA) and L‐alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L‐alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P‐388 murine leukemia resistant to cytosine arabinoside. Dose‐limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one‐day treatment repeated of PALA, 5.0 g/m2 and L‐alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1–5 and L‐alanosine, 60 mg/m2/d 1‐5.