Abstract
Eighteen patients with malignancies refractory to conventional forms of therapy were treated with 5-day continuous infusions of PALA and 5-FU. PALA was administered at a dose of 940 mg/m2/day. 5-FU was initially given at a dose of 180 mg/m2/day and was incrementally increased to 325 mg/m2/day. The courses were repeated every 3-4 weeks. Mucositis and diarrhea were the dose-limiting toxic effects. Other reversible side effects included grade 2 skin rashes and nausea and vomiting. Peak plasma PALA concentrations were approximately 20 microM and occurred in conjunction with a maximum depression of leukocyte-L-aspartate transcarbamylase (ATCase) activity to 10% of baseline. Therapeutic responses occurred in one of the 13 patients with colon carcinoma and in one patient with mammary carcinoma. Responses could not be correlated with leukocyte ATCase depression. Recent data indicate that low doses of PALA (250 mg/m2) might be equally as effective in inhibiting leukocyte ATCase activity as the doses used in this study. A phase II trial has been designed at this institution employing the above doses of PALA in conjunction with escalating doses of 5-FU.
