5-Fluorouracil derivatives: a patent review

The fluorinated analog of uracil 5-FU is an antimetabolite, active against a wide range of solid tumors. The main mechanism of action consists in interfering with DNA synthesis and mRNA translation. However, patients treated with 5-FU display several side effects, a result of its nonspecific cytotoxicity for tumor cells. Numerous modifications of the 5-FU structure have been performed in order to overcome these disadvantages.

In this review, the metabolic pathways, pharmacokinetics and clinical pharmacology of 5-FU are briefly introduced. Moreover, several derivatives developed and patented, including oral 5-FU prodrugs and combinations with other active compounds, are presented. Finally, new innovative methods for administration and vehiculization of 5-FU and its derivatives are described.

The search for less toxic 5-FU derivatives, which diminish or circumvent some of its disadvantages, has allowed the development of selective antitumor prodrugs and novel methods for tissue-specific drug delivery. Although some of these oral prodrugs are being used clinically, either alone or in combination therapy with other anticancer agents, it seems that the potential of personalized medicine, including pharmacogenomics and targeted therapy with novel 5-FU derivatives, will improve the management and clinical responses of patients treated with 5-FU-based therapy.