DIPYRIDAMOLE POTENTIATES ANTIPURINE ANTIFOLATE ACTIVITY IN THE PRESENCE OF HYPOXANTHINE IN TUMOR-CELLS BUT NOT IN NORMAL-TISSUES IN-VITRO

The cytotoxicity of the antifolate inhibitors of de novo purine biosyn thesis, lometrexol (LTX) and LY309887, can be abolished by hypoxanthin e (HPX) salvage. The nucleoside transport inhibitor, dipyridamole (DP) can prevent HPX rescue from LTX growth inhibition in a cell line-spec ific manner. The studies described here have shown that, excluding col on and hematological malignancies, DP prevents HPX rescue from LTX gro wth inhibition in approximately one-third of cell lines with otherwise limited tissue specificity. The clinical dose-limiting toxicities of antipurine antifolates are to the bone marrow and gastrointestinal tra ct. In vitro models of these normal tissues were established, and the effect of DP on HPX rescue from LY309887 treatment was studied. Growth inhibition assays are not feasible in these primary cultures; therefo re, an alternative assay, cellular ATP depletion, was validated in fou r tumor cell lines as a marker of de novo and salvage purine synthesis . In LY309887-treated cells, DP prevented HPX-mediated maintenance of ATP levels only in cell lines in which DP inhibited HPX rescue from an tifolate cytotoxicity, Hence, ATP depletion is a reliable indicator of sensitivity of HPX transport to DP when direct cell growth measuremen t is impractical. In primary cultures of human hematopoetic progenitor cells and mouse small intestine, coincubation with HPX prevented LY30 9887-mediated ATP depletion, which was not blocked by DP, These data s uggest that DP would not prevent HPX rescue from antipurine antifolate growth inhibition in sensitive normal tissues, whereas activity again st certain solid human tumors would be maintained.