Summary
While N-phosphonacetyl-L-aspartic acid (PALA), an inhibitor of de novo pyrimidine biosynthesis, demonstrated a unique spectrum of activity during preclinical drug evaluation, multiple clinical trials have shown it to possess minimal clinical activity. One explanation for the disappointing results is the possibility that tumor cells are able to utilize circulating uridine in the synthesis of pyrimidines (salvage pathway). Dipyridamole, an inhibitor of nucleoside transport, has been demonstrated experimentally to potentiate the cytotoxicity of PALA significantly. In addition, this agent has a long safety record when used clinically in man. A phase I trial of this two-drug combination was therefore conducted, with a fixed oral dose of dipyridamole (50 mg/m2 every 6 h) and an escalating i. v. dose of PALA administered every 3 weeks. The dose-limiting toxicity with this schedule was diarrhea and abdominal cramping pain at a PALA dose of 3900–4200 mg/m2. Among the 65 patients participating in this trial 4 objective responses (2 partial, 2 minimal) were observed. Because of the potential for unique clinical synergy between PALA and dipyridamole further investigation should be considered.
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Supported by grant CA-23334 from the National Cancer Institute, by grant RR-00827 from the National Institutes of Health, Division of Research Resources and by a grant from Boehringer-Ingelheim Ltd. This work was conducted in part by the Clayton Foundation for Research-California Division. Dr. Howell is a Clayton Foundation Investigator. Dr. Markman is an American Cancer Society Junior Faculty Clinical Fellow
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Markman, M., Chan, T.C.K., Cleary, S. et al. Phase I trial of combination therapy of cancer with N-phosphanacetyl-L-aspartic acid and dipyridamole. Cancer Chemother. Pharmacol. 19, 80–83 (1987). https://doi.org/10.1007/BF00296262
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DOI: https://doi.org/10.1007/BF00296262