title: Role of ABC transporters in fluoropyrimidine-based chemotherapy response.
abstract: Since over 50 years, 5-fluorouracil (5-FU) is in use as backbone of chemotherapy treatment regimens for a wide range of cancers including colon, breast, and head and neck carcinomas. However, drug resistance and severe toxicities such as mucositis, diarrhea, neutropenia, and vomiting in up to 40% of treated patients often lead to dose limitation or treatment discontinuation. Because the oral bioavailability of 5-FU is unpredictable and highly variable, 5-FU is commonly administered intravenously. To overcome medical complications and inconvenience associated with intravenous administration, the oral prodrugs capecitabine and tegafur have been developed. Both fluoropyrimidines are metabolically converted intracellularly to 5-FU, which then needs metabolic activation to exert its damaging activity on RNA and DNA. The low response rates of 10-15% of 5-FU monotherapy can be improved by combination regimens of infusional 5-FU and leucovorin together with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), thereby increasing response rates to 30-40%. The impact of metabolizing enzymes in the development of fluoropyrimidine toxicity and resistance has been studied in great detail. In addition, membrane drug transporters, which are critical determinants of intracellular drug concentrations, may play a role in occurrence of toxicity and development of resistance against fluoropyrimidine-based therapy as well. This review therefore summarizes current knowledge on the role of drug transporters with particular focus on ATP-binding cassette transporters in fluoropyrimidine-based chemotherapy response.
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. Electronic address: anne.nies@ikp-stuttgart.de.
authors: Anne T
authors: AT
authors: Nies
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors: Tarek
authors: T
authors: Magdy
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany.
authors: Matthias
authors: M
authors: Schwab
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors: Ulrich M
authors: UM
authors: Zanger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001682:Biological Availability; D001692:Biological Transport; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000069287:Capecitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D005641:Tegafur / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D005641:Tegafur; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: 5-Fluorouracil; ABCC11; ABCC5; Anti-cancer drugs; Cancer therapy; Drug response; Fluoropyrimidine; Pharmacogenetics; Toxicity; Transporter