Novel oral fluoropyrimidines in the treatment of metastatic colorectal cancer

Abstract

The evolution of and rationale for fluorouracil-based strategies in the treatment of metastatic colorectal cancer are discussed, and the role of the new oral fluoropyrimidines is described. Although fluorouracil is one of the most widely used drugs in the United States for colorectal, head and neck, bladder, and breast cancer, response rates and survival times have been disappointing. Dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in the catabolism of fluorouracil, indirectly determines the drug's anticancer efficacy by regulating the availability of fluorouracil for anabolism. Recently, investigators have identified at least five compounds -capecitabine, UFT (tegafur plus uracil), eniluracil, S-1, and BOF-A2-that inhibit, destroy, inactivate, or bypass DPD's activity. Capecitabine, a prodrug of fluorouracil, circumvents DPD. UFT, S-1, and BOF-A2 contain prodrugs of fluorouracil in combination with compounds that alter DPD's activity. Fluorouracil must be administered in combination with eniluracil, an inactivator of DPD. These compounds, classified as fluoropyrimidines, can be administered orally. Oral fluoropyrimidines appear to be at least as active against metastatic colorectal cancer as conventionally administered intravenous fluorouracil, with significantly less toxicity, improved quality of life, and less expense. New oral fluoropyrimidines may ultimately provide enhanced antitumor activity to fluorouracil-containing regimens for advanced colorectal cancer.