Fluoropyrimidine resistance in colon cancer.
A significant obstacle for the management of patients with colorectal cancer is intrinsic drug resistance or in patients that respond to chemotherapy, acquired drug resistance. Drug resistance can occur through a variety of mechanisms. These include alterations in drug influx, drug efflux, intracellular metabolic activation, intracellular catabolism, through alterations in the drug's target or through numerous changes downstream of the target including alterations in genes involved in the regulation of the cell cycle, apoptosis or in DNA damage repair. In this article, the mechanisms of action and the mechanisms of resistance to the fluoropyrimidines are reviewed focusing on newer studies using tumor samples obtained from patients. Clinical trials that can potentially overcome the relevant mechanisms of resistance are described.
Gorlick
Richard
R
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. gorlickr@mskcc.org
Banerjee
Debabrata
D
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D011743:Pyrimidines / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D011743:Pyrimidines; D013940:Thymidylate Synthase; D005472:Fluorouracil