Chemotherapeutic implications in microsatellite unstable colorectal cancer

Cancer Biomark. 2006;2(1-2):51-60. doi: 10.3233/cbm-2006-21-206.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / drug therapy*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Humans
  • Microsatellite Instability / drug effects*
  • Microsatellite Repeats / drug effects*
  • Microsatellite Repeats / genetics*


  • Antineoplastic Agents