title: Rational development of capecitabine.
abstract: Capecitabine is a fluoropyrimidine carbamate that was rationally designed as an oral drug capable of mimicking continuous infusion 5-fluorouracil (5-FU) and delivering 5-FU preferentially to tumour tissue. Following extensive absorption, capecitabine is rapidly converted to 5-FU via a three-step enzymatic pathway. The final step depends on thymidine phosphorylase, an enzyme present at higher concentrations in malignant compared with normal tissue. This results in the delivery of 5-FU preferentially to the tumour site. Capecitabine has demonstrated high activity in preclinical xenograft models for a wide range of human solid tumours, including those resistant to 5-FU. Phase I studies have determined the maximum tolerated dose (MTD) of capecitabine and identified a number of dosage regimens, which were subsequently evaluated in a randomised, phase II study as first-line treatment for metastatic colorectal cancer. This established an intermittent regimen of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period as the most appropriate regimen for further clinical development.
authors.affiliation: Divisione Oncologia Medica, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. mventur@hp380.ist.unige.it
authors.forename: M
authors.initials: M
authors.lastname: Venturini
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069287:Capecitabine; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil