A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU

Abstract

Thirty-four patients were treated with N-(phosphonacetyl)-L-aspartate (PALA) at a dose of 850 mg/m2/day x 5 by continuous intravenous infusion (days 1-5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300-630 mg/m2/day x 5 by continuous intravenous infusion (days 2-6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m2/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 micrograms/ml.

In vitro and in vivo anti‐tumor activity of L‐glutamic acid γ‐monohydroxamate against L1210 leukemia and B16 melanoma

“…On this basis, Collins and Stark (1971) synthesized N-(phosphonacety1)-L-aspartic acid (PALA), an analogue of L-asparagine, which interacts with aspartate transcarbamylase, an early enzyme in the pathway of de novo pyrimidine nucleotide biosynthesis. This compound is now in phase-I1 clinical trials (Weiss et al, 1982). Considerable interest has recently been devoted to the design of enzyme inactivators called suicide inactivators.…”

Cell cycle phase perturbations by 6-diazo-5-oxo-L-norleucine and acivicin in normal and neoplastic human cell lines

“…These analogues of glutamine, however, have limited potential when used as single agents in the treatment of cancer in man because of severe toxicity that prevents dose escalation into the required therapeutic range (Sklaroff et al, 1980;Weiss et al, 1982;LePage & Loo, 1973). Co-administration of glutamine reduces markedly the concentration of glutamine in the tumour-bearing host making it possible to utilize considerably lower doses of the analogue, and this has resulted in improvement of the therapeutic index (Roberts & Rosenfeld, 1980;Roberts et al, 1979;Holcenberg, 1979).…”

N-(Phosphonoacetyl)amino phosphonates. Phosphonate analogs of N-(phosphonoacetyl)-L-aspartic acid (PALA)

“…The possibility of using PALA in polychemotherapy is also very promising since it was found to be synergistic with several popular anticancer drugs including fluorouracil, alanosine, acivicin, methotrexate, and pyrofurazin.11, [14][15][16][17][18][19][20] Although PALA is a promising anticancer agent, its usefulness in human therapy seems to be limited. It fails to inhibit pyrimidine biosynthesis in vivo as strongly as f Technical University of Wroclaw.…”