5'-DFUR, A NEW ANTI-CANCER AGENT SELECTIVELY ACTIVATED IN TUMOR-CELLS .1. ROLE OF URIDINE PHOSPHORYLASE FOR ANTI-TUMOR ACTIVITY OF 5'-DEOXY-5-FLUOROURIDINE

Abstract

5''-Deoxy-5-fluorouridine (5''-DFUR) was parenterally and orally effective on various transplantable tumors [mouse sarcoma 180 cells, mouse leukemia L-1210 cells, mouse leukemia P-388 cells] and its activity was better than that of other fluorinated pyrimidines. Like 5-fluorouracil and 2''-deoxy-5-fluorouridine (FUdR), 5''-DFUR was ineffective on L1210 leukemia resistant to 5-fluorouracil suggesting that it would exert its antitumor activity through converted 5-fluorouracil. In tissue culture, 5''-DFUR inhibited the growth of various tumor cells similarly to other fluorinated pyrimidines; 5''-DFUR was unique in that uridine completely reversed its inhibitory effect. Enzymological study clarified that uridine inhibited the conversion of 5''-DFUR to 5-fluorouracil by a uridine phosphorylase, in parallel to its reverse effect on cell growth inhibition by 5''-DFUR. A subline of L-1210 leukemia resistant to 5''-DFUR but not to 5-fluorouracil lacked the uridine phosphorylase. 5''-DFUR apparently is a depot form of 5-fluorouracil which can be promptly activated by uridine phosphorylase. The uridine phosphorylase was abundant in sarcoma-180 solid tumor, leading to a significantly higher concentration of converted 5-fluorouracil in this tumor than in other normal tissues. This provides a good explanation for the high chemotherapeutic index of 5''-DFUR against this tumor, which may be applicable also for other tumors.