The Mayo/NCCTG Experience with 5-Fluorouracil and Leucovorin in Adjuvant Advanced Colorectal Cancer

Hundreds of studies have evaluated the activity of fluorinated pyrimidines in the treatment of colorectal and other cancers. The background data regarding the mechanisms of action of these agents is discussed elsewhere and will be mentioned here only briefly to provide historical context. Fluorinated pyrimidines, of which 5-fluorouracil (5-FU) is the most commonly used, exert their antineoplastic effect in part by inhibiting the activity of the enzyme thymidylate synthase (TS) critical in the de novo synthesis of DNA. They also are incorporated into RNA and DNA, which may contribute to their cytotoxic effects. A number of different fluorinated pyrimidines have been administered as single agents and as a part of combinations with other cytotoxic drugs. Biochemical modulation of fluorinated pyrimidines designed to improve their therapeutic index has been evaluated extensively. Leucovorin is the most common biochemical modulator used with fluorinated pyrimidines.