Thymidylate synthetase inhibition in malignant tumors and normal liver of patients given intravenous 5-fluorouracil.

Single surgical biopsies of solid tumor were obtained at 20 to 240 min after drug administration in 21 patients given first-dose bolus i.v. 5-fluorouracil (5-FUra), 500 mg/sq m, and assayed for 5-fluorodeoxyuridylate (FdUMP), deoxyuridylate (dUMP), total thymidylate synthetase (TS), and non-FdUMP-bound, free enzyme. Nineteen patients had cancer of gastrointestinal origin, 13 of these colorectal, and 2 patients had breast adenocarcinoma. In 9 patients, synchronous biopsies of surgically normal liver were obtained along with samples of hepatic tumors metastatic from gastrointestinal sites. Total TS averaged 4.18 pmol/g in the malignant tissues and 2.23 pmol/g in liver. FdUMP levels in the gastrointestinal tumors were higher than in normal liver, were highest at the earliest time interval studied, 20 to 30 min, and appeared to decrease exponentially through 120 min. TS inhibition averaged 70 to 80% in gastrointestinal tumor biopsies and less than 50% in normal liver. Levels of dUMP were low and varied little with time. Those gastrointestinal tumors with higher FdUMP:dUMP ratios showed significantly greater TS inhibition. Tumors of 3 patients who benefited from 5-FUra therapy (1 patient with colonic adenocarcinoma and the 2 patients with breast adenocarcinoma) showed greater TS inhibition than did tumors of remaining patients. It is concluded that the apparent time course changes observed in FdUMP, dUMP, and TS in the grouped data are qualitatively similar to findings of murine studies in vivo and that the relationship between FdUMP:dUMP ratios and TS inhibition are consistent with established in vitro enzymic kinetics. Thus, biopsies of tumors at short time periods after 5-FUra administration may be usefully studied for biochemical parameters of TS inhibition, with the objectives of correlation of sensitivity to subsequent 5-FUra therapy and clarification of mechanisms of drug resistance.