Depletion of O6-methylguanine-DNA methyltransferase by O 6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines

Jun Murakami, You Jin Lee, Susumu Kokeguchi, Hidetsugu Tsujigiwa, Jun Ichi Asaumi, Hitoshi Nagatsuka, Kazuhiro Fukui, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara

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38 Citations (Scopus)

Abstract

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 antitumor 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 O 6-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 O 6-BG. Depletion of MGMT by O6-BG enhanced the antitumor 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.

Original languageEnglish
Pages (from-to)1461-1467
Number of pages7
JournalOncology reports
Volume17
Issue number6
Publication statusPublished - Jun 1 2007

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Keywords

  • 5-Fluorouracil
  • O -benzylguanine
  • O- methylguanine-DNA methyltransferase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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