ABSTRACT
Hundreds of articles in the medical literature explore the activity of fluorinated pyrimidines in the treatment of colorectal and other cancers. As a result, the background data regarding the mechanisms of action are well known to oncologists, and will be reviewed here only briefly to provide historical context. Fluorinated pyrimidines, of which 5-fluorouracil (5FU) is the most ubiquitous, exert their antineoplastic effect at least in part by inhibiting the activity of the enzyme thymidylate synthase (TS). TS inhibition interferes with DNA synthesis in dividing cells, preventing successful mitosis, and often causing lethal damage to the parent cell. A number of different fluorinated pyrimidines have been administered as single agents and as part of combinations with other cytotoxic drugs. Often fluorinated pyrimidines are combined with agents designed to improve their therapeutic index by preferentially sensitizing tumor but not host cells to the agent(s). The latter drugs, which are not cytotoxic themselves, are commonly referred to as biochemical modulators. Leucovorin is one of the most commonly employed biochemical modulators, and is principally used with fluorinated pyrimidines. The Mayo Clinic/North Central Cancer Treatment Group (NCCTG) regimen of 5-FU and leucovorin is one example of biochemical modulation of a fluorinated pyrimidine that is in common use.
