New drugs in therapy of colorectal cancer: preclinical studies

For years, 5-fluorouracil (5-FU) was the only chemotherapeutic agent for the treatment of patients with advanced colorectal cancer. Based on laboratory data, modulation of 5-FU by leucovorin (LV) was proven to be an active alternative. In addition, a number of 5-FU prodrugs and antifolate antimetabolites became available for preclinical and clinical evaluation. With the 5-FU prodrugs, the overall aim was to improve the therapeutic efficacy and selectivity of 5-FU and to provide an oral form of therapy. In preclinical systems, several of the 5-FU prodrugs, eg, capecitabine, uracil/ ftorafur (UFT)/LV, and S- , are active and offer significant therapeutic advantages over 5-FU/LV. A direct and specific new thymidylate synthase (TS) inhibitor, Tomudex (raltitrexed, ZDI694; Zeneca Pharmaceuticals, Macclesfield, UK), is active in several preclinical and clinical settings. The major focus of this report will be on the preclinical development of selected fluoropyrimidine prodrugs.