Published in Cancer Detection and Prevention 1997; 21(4):340-345.

Preventive Effect of 1-(2-Tetrahydrofuryl)-5-Fluorouracil in Combination with Uracil on Colonic Carcinogenesis Induced by 1 ,2-Dimethylhydrazine in Rats

Shinobu Sakamoto MDa, Yasuyuki Kawachi MDb, Takeo Iwama MDb, Kunio Tsukada MDb, Tetsuro Sagara MDb, Saburo Murakami MDb, Hideki Kudo MDa, Isao Okayasu MDC

aMedical Research Institute; bSecond Department of Surgery, Tokyo Medical and Dental University, Tokyo; cDepartment of Pathology, School of Medicine, Kitasato University, Kanagawa, Japan

Address all correspondence and reprint requests to: Shinobu Sakamoto, M.D., Medical Research Institute, Tokyo Medical and Dental University. 1-5-45. Yushima, Bunkyo-ku. Tokyo 113, Japan.

ABSTRACT: Thymidylate synthetase (TS) and thymidine kinase (TK) are key enzymes in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively. A high incidence of colorectal adenocarcinomas with varied grades of cell differentiation can be induced by 1 ,2-dimethylhydrazine (DMH) in rats. The marked increases of TS and TK activities were found in the poorly and well-differentiated adenocarcinomas of the colon, respectively. Oral administration of 1 -(2-tetrahydrofuryl)-5-fluorouracil in combination with uracil (UFT) markedly reduced the number and accumulated area of colonic carcinomas, and TS activity in the poorly differentiated adenocarcinomas. A potential balance between the de novo and the salvage pathways for pyrimidine nucleotide synthesis was suggested to be related with the histopathological grades of cell differentiation. Suppression of colonic TS activity by UFT administration reduced the colonic carcinogenesis and the potency of the poorly differentiated adenocarcinomas of the colon.

KEY WORDS: colorectal adenocarcinoma, 5-fluorouracil, histological differentiation, thymidine kinase, thymidylate synthetase.