Dihydrofolate reductase activity of leukemia L1210 during development of methotrexate resistance

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

“…The mechanism of action of Dip is poorly understood. Although Scholtissek (9) suggested that it competes with nucleosides for a complex between nucleoside kinases and a membrane component, the finding that Dip interferes with nucleoside uptake in a kinase-deficient cell makes this doubtful (10 shown to be small (12), and in the case of secondary resistance to MTX, where greater intracellular drug concentrations may overcome the most usual forms of resistance (17)(18)(19)(20)(21)(22). When administrated in vivo, MTX gives rise to a variety of metabolites, and when tritiated MTX has been used, tritiated water also has appeared (23)(24)(25).…”

“…After being counted, tumor cells were centrifuged at 500 x g for 10 min, washed once with Eagle's minimal essential medium (ME medium), and resuspended in ME medium at 1 x 106 cells per ml. After being submitted to different experimental conditions, 1-ml aliquots received pulses (30 min at 37°C) with 0.2 ,uCi ( [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Ci/mmol). The pulses were terminated by the addition of 0.1 ml of 0.1 M PPj, 0.2 ml of DNA carrier (2.5 mg/ml), 0.2 ml of H20, and 0.25 ml of 12.5% perchloric acid.…”