Evolving 5-fluorouracil therapy to achieve enhanced efficacy-past and current efforts of researchers

5-fluorouracil (5-FU) therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation (BCM) with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur (FT), followed by tegafur-uracil (UFT) and tegafurgimeracil-potassium oxonate (S-1) as combined products based on BCM. In the current standard treatment for gastrointestinal cancers, anticancer 5-FU derivatives serve as a platform for combination regimens with other cytotoxic agents or molecular-targeted drugs. To provide further improvements in anticancer therapy outcomes, novel molecular-targeted agents, immune checkpoint inhibitors, and other drugs are being developed, but 5-FU remains an attractive target that shows further potential for increased efficacy. In the future, the evolution of anticancer therapy with 5-FU derivatives is expected to continue via a variety of approaches.