title: Chemotherapeutic implications in microsatellite unstable colorectal cancer.
abstract: Chemotherapy for colorectal cancer is currently offered to patients based on the stage of their cancer, and there is evidence to show an overall survival benefit with 5-fluorouracil-based (5-FU) therapy for patients with lymph node metastasis who receive it. The pathogenesis of colorectal cancer involves genomic instability, with about 15% of tumors demonstrating a form of genomic instability called high-frequency microsatellite instability (MSI-H) and due to loss of DNA mismatch repair function, and the remainder of colorectal tumors lacking MSI-H with retained DNA mismatch repair function and called microsatellite stable (MSS), with a large proportion of these tumors demonstrating another form of genomic instability called chromosomal instability. There is now evidence to show that the form of genomic instability that is present in a patient's colorectal cancer may predict a survival benefit from 5-FU. In particular, patients whose colorectal tumors have MSI-H do not gain a survival benefit with 5-FU as compared to patients with MSS tumors. In vitro evidence supports these findings, as MSI-H colon cancer cell lines are more resistant to 5-FU compared to MSS cell lines. More specifically, components of the DNA mismatch repair system have been shown to recognize and bind to 5-FU that becomes incorporated into DNA and which could be a trigger to induce cell death. The binding and subsequent cell death events would be absent in colorectal tumors with MSI-H, which have lost intact DNA mismatch repair function. These findings suggest that: (a) tumor cytotoxicity of 5-FU is mediated by DNA mechanisms in addition to well-known RNA mechanisms, and (b) patients whose tumors demonstrate MSI-H may not benefit from 5-FU therapy. Future studies should include a better understanding of the cellular mechanisms of the DNA recognition of 5-FU, multi-centered prospective trials investigating the survival benefit of 5-FU based on genomic instability, and the investigation of alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival.
authors.affiliation: Department of Medicine, University of California, and VA San Diego Healthcare System, CA 92161, USA.
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Jo
authors.forename: John M
authors.initials: JM
authors.lastname: Carethers
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D053842:Microsatellite Instability / Q000187:drug effects*; D018895:Microsatellite Repeats / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents