SELECTIVE POTENTIATION OF LOMETREXOL GROWTH-INHIBITION BY DIPYRIDAMOLE THROUGH CELL-SPECIFIC INHIBITION OF HYPOXANTHINE SALVAGE

The novel antifolate lometrexol (5,10-dideazatetrahydrofolate) inhibit s de novo purine biosynthesis, and cc-incubation with hypoxanthine abo lishes its cytotoxicity. The prevention of hypoxanthine rescue from an antipurine antifolate by the nucleoside transport inhibitor dipyridam ole was investigated for the first time in nine human and rodent cell lines from seven different tissues of origin, In A549, HeLa and CHO ce lls, dipyridamole prevented hypoxanthine rescue and so growth was inhi bited by the combination of lometrexol, dipyridamole and hypoxanthine, but in HT29, HCT116, KK47, MDA231, CCRF CEM and L1210 cells dipyridam ole had no effect and the combination did not inhibit growth. Dipyrida mole inhibited hypoxanthine uptake in A549 but not in CCRF CEM cells. Dipyridamole prevented the hypoxanthine-induced repletion of dGTP pool s, depleted by lometrexol, in A549 but not in CCRF CEM cells, Thus, th e selective growth-inhibitory effect of the combination of lometrexol, dipyridamole and hypoxanthine is apparently due to the dipyridamole s ensitivity (ds) or insensitivity (di) of hypoxanthine transport. Both the human and murine leukaemic cells are of the di phenotype. If this reflects the transport phenotype of normal bone marrow it would sugges t that the combination of lometrexol, dipyridamole and hypoxanthine mi ght be selectively toxic to certain tumour types and have reduced toxi city to the bone marrow.