Dipyridamole inhibits reversion by thymidine of methotrexate effect and increases drug uptake in Sarcoma 180 cells.

Publisher Website
Google Scholar
Abstract
The combined effect of methotrexate (MTX) with dipyridamole, an inhibitor of nucleoside transport, was studied in ascitic sarcoma 180 cells [mouse]. It was determined that 10 .mu.M MTX inhibits by > 90% deoxy[1H]uridine incorporation into DNA and that this MTX concentration inhibits DNA synthesis as revealed by deoxy[3H]cytidine but not [3H]thymidine incorporation into DNA. Exogenous thymidine (.gtoreq. 1 .mu.M) in the cell culture medium enhances DNA synthesis in nontreated cells and fully restores it in MTX-treated cells, whereas hypoxanthine has no appreciable effect of DNA synthesis. Dipyridamole inhibits deoxy[3H]cytidine and [3H]thymidine uptake by these cells (IC50 = 0.2 and 3 .mu.M, respectively) and blocks the increase in TTP pool produced by 1 .mu.M thymidine in MTX-treated cells (23.1 .+-. 4.7 pmol per 1 .times. 106 cells vs. 80.4 .+-. 18.9 pmol per 1 .times. 106 cells). Dipyridamole at 10 .mu.M enhances [3H]MTX accumulation by sarcoma 180 cells and diminishes the efflux of the drug in previously loaded cells. The combination of inhibitors of the de novo pathway for pyrimidine biosynthesis, such as MTX, with inhibitors of the salvage pathway, such as dipyridamole, may increase the cytotoxic activity of MTX alone.