Modulation of the activity of PALA by dipyridamole

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.