INFLUENCE OF PH ON THE UPTAKE OF 5-FLUOROURACIL INTO ISOLATED TUMOR-CELLS

To investigate the possible dependence of 5-fluorouracil (5FU) uptake in tumours on the intra- (pH(i)) and extracellular (pH(e)) pH, a pH gr adient (Delta pH) was imposed across the plasma membrane of ascites tu mour cells in vitro, similar to that known to occur in some solid tumo urs in vivo, by incubation in media of pH(e) 5-8. A greater than or eq ual to 2:1 (intracellular/extracellular) accumulation of radiolabelled 5FU occurred after 5 min incubation of the cells with 0.5 mM 5FU at p H(e) of 5.0, 5.5 or 6.0. 5FU metabolism is slow under these conditions , and 5FU uptake was not affected by longer incubations up to 20 min, nor by the absence of a sodium gradient. pH, was estimated from the di stribution of the weak acid, 5,5-dimethyl-2,4-oxazolidione ([C-14]DMO) across the cell membrane. There was significant correlation between t he intracellular/extracellular 5FU ratio and pH(e) (from pH(e) 6-8), D elta pH and pH(i) (P < 0.02). Similar results were obtained with HT29 cells. incubation with a drug that made plasma membranes permeable to H+ significantly decreased 5FU uptake in Lettre cells. The co-transpor t of 5FU may occur on a proton symport using the proton motive force o f the Delta pH.