We analyzed
dihydropyrimidine dehydrogenase (DPD) activity (radioenzymatic assay) and
5-fluorouracil (5-FU) cytotoxicity (MTT test) in the absence 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 human 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 suggested that combined fluoropyrimidine and
uracil treatment of
tumors with high basal DPD, elicits a greater antitumor effect than fluoropyrimidines alone, since
uracil could inhibit the degradation of
5-FU in the
tumor. UFT, an oral fluoropyrimidine combined with
uracil, is expected to be more effective in such
tumors.