ENHANCING 5-FLUOROURACIL CYTOTOXICITY BY INHIBITING DIHYDROPYRIMIDINEDEHYDROGENASE-ACTIVITY WITH URACIL IN HUMAN TUMOR-CELLS

We analyzed dihydropyrimidine dehydrogenase (DPD) activity (radioenzym atic assay) and 5-fluorouracil (5-FU) cytotoxicity (MTT test) in the a bsence or presence of uracil in two human cancer cell lines, MIAPaCa-2 (pancreas tumor) and HuTu80 (duodenum tumor). Basal DPD activities in both were comparatively high; MIAPaCa-2, 101 and HuTu80, 153 pmol/min /mg protein, respectively. Twenty mu g/ml of uracil, a dose which did not influence cell proliferation, enhanced 5-FU cytotoxicity; MIAPaCa- 2, 2.0-fold and HuTu80, 1.5-fold, respectively. Uracil inhibited both DPD activity and cell growth in a concentration-dependent manner, and exhibited maximum effect at molar ratios to 5-FU of more than 10 (DPD activity, almost complete inhibition; growth-inhibitory effect, about a 30% increase). In addition, the cytosolic DPD activity of OCC-1 huma n head and neck tumors, collected following the oral administration of ss mg/kg of uracil to tumor-bearing nude mice, decreased to about 50% of that of OCC-1 tumors not treated with uracil. These findings sugge sted that combined fluoropyrimidine and uracil treatment of tumors wit h high basal DPD, elicits a greater antitumor effect than fluoropyrimi dines alone, since uracil could inhibit the degradation of 5-FU in the tumor. UFT, an oral fluoropyrimidine combined with uracil, is expecte d to be more effective in such tumors.