Thymidylate synthetase activity and fluorouracil sensitivity of human colonic cancer and normal mucosal tissue preparations

Abstract

This study compares thymidylate synthetase activity and certain aspects of fluorinated pyrimidine metabolism in tissue preparations derived from human colonic adenocarcinoma and from normal colonic mucosa. The purpose was to define differences that might be sufficient to explain the selective antitumor response of some colonic adenocarcinomas to 5-fluorouracil (FU) chemotherapy. Some carcinomas had much greater thymidylate synthetase activity than did other carcinomas and all normal mucosal preparations. Such carcinomas may be highly reliant on thymidylate synthetase and hence susceptible to its inhibition. Similarly, the smaller amount of FdUMP dephosphorylation found in all carcinomas compared with autologous normal mucosal preparations might result in prolonged thymidylate synthetase inhibition. In addition, greater thymidylate synthetase inhibition was produced by 1 X 10(-4) M FU in an occasional tumor than was found in normal mucosal preparations.