5-fluorouracil: a pharmacological paradigm in the use of cytotoxics.
1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.
Thomas
D M
DM
Department of Medical Oncology, Royal Melbourne Hospital, Victoria, Australia.
Zalcberg
J R
JR
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil