The sensitization of tumour cells to chemotherapy or radiotherapy is known as ’chemosensitization’ or ’radiosensitization’, respectively.

 An example of chemosensitization is the combined use of 5-fluorouracil (5-FU) and leucovorin (5’-formyltetrahydrofolate). A pure sensitizer should not really have innate cytotoxic properties, and leucovorin fulfills this criterion.

5-FU is the most active anti-neoplastic agent in the treatment of advanced colorectal cancer. It acts through its conversion product - 5-fluoro-2’deoxy-5’monophosphate (FdUMP) - inhibiting thymidylate synthase and, subsequently, DNA synthesis.

A folate cofactor can increase the stability and activity of 5-FU through the formation of a covalent ternary complex.

Resistance mechanisms against 5-FU include aberrations in its metabolism, alterations of thymidylate synthase - for instance, gene amplification - and altered kinetics with respect to nucleotides or folates.

Increasing intracellular levels of reduced folate methylenetetrahydrofolate (CH2THF) can improve the binding of FdUMP to thymidylate synthase and overcome some resistance against 5-FU.

Leucovorin has been used to expand the intracellular concentration of CH2THF and has been shown to increase the in vitro and in vivo toxicity of 5-FU by enhancing enzymatic binding in many cancer cell lines.

Although leucovorin does not have antitumour activity on its own, the advanced colorectal cancer meta-analysis project showed that 5-FU and leucovorin generated significantly superior response rates compared with bolus single-agent 5-FU (23% versus 11%); however, this did not result in significantly improved overall survival. In vitro, it seems that leucovorin sensitizes both tumour and normal cells to 5-FU.