5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical Development

5-Fluorouracil (5-FU) and 5-fluoro-2′-deoxyuridine (FdUrd) are pyrimidine analogs that have been partof the therapeutic armamentarium for a variety of solid tumorsfor over forty years. 5-FU has customarily required intravenousadministration due to poor and erratic oral bioavailability,while FdUrd has generally been employed for regionaladministration to the liver or the peritoneal cavity. A greatdeal of knowledge has been gained concerning the cellularpharmacology and mechanism of action of 5-FU since it was firstsynthesized in the late 1950's. A more thorough understanding ofthe factors influencing the metabolic activation of 5-FU and itscellular effects has generated considerable interest in combiningit with both modulatory agents such as leucovorin andmethotrexate that enhance its metabolism or cytotoxic effects.In addition, 5-FU has also been employed to enhance thetherapeutic activity of other antineoplastic agents or modalitiessuch as cisplatin and ionizing radiation with which it cansynergize. Appreciation of the clinical pharmacology of 5-FU andFdUrd have led to a variety of schedules that are clinicallyuseful. The preelinical and clinical pharmacology of 5-FU isreviewed to provide a basis for exploring the novel approachesto permit oral administration of 5-FU or its prodrugs that willbe described in other articles in this issue.