Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines

Oncol Rep. 2007 Jun;17(6):1461-7.


O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose expression is controlled by its promoter methylation. A cell that expresses a low amount of MGMT is known to be more sensitive to the antiproliferative effects of alkylating agents. We have previously shown that the colorectal cancer patients treated with 5-fluorouracil (5-FU) as adjuvant chemotherapy had a better prognosis when the tumor revealed hypermethylation in its MGMT promoter. Therefore, we sought to investigate the relationship between the expression levels of MGMT and the anti-tumor effect of 5-FU in vitro by using two colon adenocarcinoma and four oral cancer cell lines with a variety of MGMT expression. We also investigated the effects of MGMT depletion by O6-benzylguanine (O6-BG), a potent inhibitor of MGMT. The 5-FU treatment uniformly depleted protein and mRNA expression of MGMT in all cell lines examined. Cell lines expressing low levels of MGMT were sensitive to 5-FU. On the other hand, cells expressing high levels of MGMT were less sensitive to 5-FU. The 5-FU treatment exhibited a better antiproliferative effect on the cells expressing high levels of MGMT by the pretreatment of O6-BG. Depletion of MGMT by O6-BG enhanced the anti-tumor effect of 5-FU. Assessment of the levels of MGMT expression in cancer cells and the control of its expression could contribute to the effective chemotherapy by 5-FU especially in patients who previously were considered as low-responsive individuals whose tumors have high levels of MGMT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / enzymology*
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Fluorouracil / pharmacology*
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology
  • Humans
  • Mouth Neoplasms / enzymology*
  • O(6)-Methylguanine-DNA Methyltransferase / analysis
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors*
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • O(6)-benzylguanine
  • Guanine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Fluorouracil