Modulation of the activity of PALA by dipyridamole.

Abstract

PALA is thought to inhibit an early step in de novo pyrimidine synthesis, causing depletion of intracellular pyrimidine nucleotides. Dipyridamole, a nucleoside transport inhibitor which can block restoration of nucleotide levels via the salvage pathway, was tested for its ability to augment the cytotoxicity of PALA against normal and malignant human cells in vitro. At the clinically relevant concentration of 1 microM, dipyridamole increased the cytotoxicity of PALA against a melanoma, a colon carcinoma, a promyelocytic leukemia (HL-60), and normal marrow (CFU-GM) in clonogenic assays. Dipyridamole produced 50% inhibition of uridine uptake in these cells at concentrations of less than 0.1 microM and reduced the LD50 of PALA by approximately 50% in mice. These results indicate that dipyridamole can markedly potentiate the activity of PALA in vitro and in vivo.

• Authors: T C Chan, B Young, M E King, R Taetle, S B Howell
• Journal: Cancer treatment reports (Cancer Treat Rep) Vol. 69 Issue 4 Pg. 425-30 (Apr 1985) ISSN: 0361-5960 [Print] United States
• PMID: 3857969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Organophosphorus Compounds
• Pyrimidine Nucleosides
• Tritium
• Aspartic Acid
• Dipyridamole
• sparfosic acid
• Phosphonoacetic Acid
• Uridine

Topics

• Animals
• Aspartic Acid (analogs & derivatives, therapeutic use, toxicity)
• Biological Transport (drug effects)
• Cell Line
• Colonic Neoplasms (drug therapy, metabolism)
• Dipyridamole (pharmacology)
• Drug Interactions
• Humans
• In Vitro Techniques
• Lethal Dose 50
• Leukemia, Myeloid (drug therapy, metabolism)
• Melanoma (drug therapy, metabolism)
• Mice
• Mice, Nude
• Organophosphorus Compounds (therapeutic use)
• Phosphonoacetic Acid (analogs & derivatives, therapeutic use, toxicity)
• Pyrimidine Nucleosides (metabolism)
• Tritium
• Uridine (metabolism)