Demonstration in vitro of inhibition in normal rat tissues yet stimulation in Jensen sarcoma cells of 5-fluorouracil anabolism by purine nucleosides

It has been shown previously that the ability of tumor cells to anabolize 5-fluorouracil (FUra) to nucleotides can often be enhanced by exposing the cells to various purine nucleosides. Increases in FUra cytotoxicity have been observed to accompany this enhancement. In the present study the effects of purine nucleosides on FUra anabolism in rat tumor cells and in normal rat tissues sensitive to FUra were compared. Pieces of small intestine (SI), bone marrow suspensions (BM) and Jensen tumor cells were incubated in culture medium at 370 for 1 hr in the presence (or absence) of a selected purine nucleoside, then (2-14C)FUra was added and the incubation was continued for another hr. Incorporation of radioactivity into the trichloroacetic acid-insoluble fraction in each case was determined as a measure of FUra anabolism. Inosine, adenosine and N6-methyl-adenosine, 1 mM, stimulated FUra incorporation into the acid-insoluble fraction 2-3 fold in the tumor cells but inhibited this incorporation 59-70% in SI and 31-70% in BM. Attempts to further suppress FUra anabolism in the normal tissues resulted in a maximal inhibition of 92% in SI, using 1 mM alloxanthine, and a maximal inhibition of 84% in BM, employing combined 1 mM alloxanthine and 1 mM 5-aminoimidazole-4-carbox-amide ribonucleoside. These data suggest ways of selectively altering FUra anabolism in normal tissue and in tumor tissue of the tumor-bearing rat to improve the therapeutic index of FUra