Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review

Abstract

Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro-and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines.In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation.The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented.The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further. The Oncologist 2002;7:288-323 The Oncologist 2002;7:288-323 www.TheOncologist.com Correspondence: M. Malet-Martino, Ph.D., Groupe de RMN Biomédicale, Laboratoire des IMRCP (UMR CNRS 5623), Université Paul Sabatier, 118, route de Narbonne, 31062 Toulouse Cédex, France. Telephone: 33-561-556271; Fax: 33-561-557625; e-mail: martino@chimie.ups-tlse.fr Received January 24, 2002; accepted for publication April 5, 2002. ©AlphaMed Press 1083-7159/2002 The Oncologist ® LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Define the main oral prodrugs of fluorouracil.2. Know the indications of the new oral prodrugs of fluorouracil.3. Review the main toxicities and drug interactions of oral prodrugs of fluorouracil.4. Evaluate the benefit(s) of using an oral prodrug of fluorouracil compared with classical treatments.Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com CME CME by guest on http://theoncologist.a...

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

“…Thymidylate synthase, a critical target for fluoropyrimidines, catalyses the methylation of deoxyuridine monophosphate to deoxythymidine monophosphate, an essential step in DNA biosynthesis (Malet-Martino and Martino, 2002). When the pretreatment biopsy specimens were analysed, high expression of TS was observed in 8% of the responders and in 28% of the nonresponders, without significant difference.…”

“…Several kinds of fluoropyrimidines are now in use. S-1 is a novel fluoropyrimidine consisting of tegafur, 5-chloro-2, 4-dihydroxypyrimidine (CDHP, a strong inhibitor of dihydropyrimidine dehydrogenase, 5-FU-catabolizing enzyme) and potassium oxonate with a molar ratio of 1 : 0.4 : 1 (Malet-Martino and Martino, 2002). S-1, especially in combination with cisplatin, shows a promising effectiveness with acceptable toxicities against gastric, pancreatic and non-small-cell lung cancers (Schoffski, 2004;Yoshida et al, 2005).…”

In vitro evaluation of cancer-specific NF-κB-CEA enhancer–promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines

“…Thymidine phosphorylase is a key enzyme for CAP, a 5-FU prodrug (Malet-Martino and Martino, 2002). As the TP activity in various cancers is highly heterogeneous, the clinical response of cancer patients to CAP remains relatively low (Malet-Martino and Martino, 2002).…”

“…Capecitabine (CAP), a prodrug of 5-FU (Malet-Martino and Martino, 2002;Petty and Cassidy, 2004), has been approved as a first line therapeutic agent for colorectal cancer (CRC) chemotherapy. Capecitabine is converted into 5-FU in vivo by a threeenzyme-catalysed process.…”

Phase II study of oral S‐1 for treatment of metastatic colorectal carcinoma

“…6 Nonetheless, CVI performed using a portable pump and an indwelling catheter is challenging and may induce phlebitis or infection originating at the injection site and requiring long-term hospitalization; thus, oral anticancer agents have been developed to address this problem. 7 The results of large Phase III studies of oral capecitabine and the combination of tegafur ϩ uracil (UFT) with LV were reported recently and demonstrated survival benefits that were equivalent to those achieved using intravenous 5-FU ϩ LV. 8 -11 Oral chemotherapy has major advantages over intravenously administered treatment in terms of pharmacoeconomic considerations and patient preferences, because oral treatment can be administered on an outpatient basis, thereby reducing the length of patients' hospital stays.…”