Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas.
OBJECTIVE
The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the cytotoxic effect of alkylating agents on tumor cells. The presence of two nonconsensus glucocorticoid-responsive elements in the human MGMT promoter region indicates the potential regulation of MGMT expression by glucocorticoid agents. This study was performed to elucidate whether dexamethasone affects the expression of MGMT in glioblastoma multiforme (GBM) cells, thereby limiting the benefit of chemotherapeutic alkylating agents.


METHODS
Four GBM cell lines (A172, T98G, U138MG, and U87MG) were exposed to the alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) with or without dexamethasone. The expression levels of MGMT were correlated with the cytotoxic effects of ACNU in GBM cells. In the presence of ACNU alone, dexamethasone alone, and the combination of both agents, messenger RNA expression of MGMT was induced to varying degrees with the highest increases seen in the later conditions. This dexamethasone-dependent induction of the MGMT gene was even observed in U87MG cells in which the promoter is methylated, although the absolute expression of MGMT mRNA was the lowest in that cell line. The induction of MGMT by dexamethasone was associated with an increased resistance of these cells to ACNU.


CONCLUSIONS
These results indicate that dexamethasone-mediated upregulation of MGMT limits the efficiency of alkylating agents in the treatment of malignant gliomas.
Ueda
Shigeo
S
Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan. uedas@post.saga-med.ac.jp
Mineta
Toshihiro
T
Nakahara
Yukiko
Y
Okamoto
Hiroaki
H
Shiraishi
Tetsuya
T
Tabuchi
Kazuo
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015376:Nimustine / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D015376:Nimustine; D003907:Dexamethasone; D019853:O(6)-Methylguanine-DNA Methyltransferase