IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide.

Abstract	Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.
Authors	Atsushi Natsume, Dai Ishii, Toshihiko Wakabayashi, Takaya Tsuno, Hisashi Hatano, Masaaki Mizuno, Jun Yoshida
Journal	Cancer research (Cancer Res) Vol. 65 Issue 17 Pg. 7573-9 (Sep 01 2005) ISSN: 0008-5472 [Print] United States
PMID	16140920 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents, Alkylating Tumor Suppressor Protein p53 Interferon-beta Dacarbazine O(6)-Methylguanine-DNA Methyltransferase Temozolomide
Topics	Antineoplastic Agents, Alkylating (administration & dosage, pharmacology) Antineoplastic Combined Chemotherapy Protocols (pharmacology) Cell Line, Tumor DNA Methylation DNA Repair (genetics) Dacarbazine (administration & dosage, analogs & derivatives, pharmacology) Down-Regulation (drug effects) Drug Resistance, Neoplasm Drug Synergism Gene Expression Regulation, Enzymologic (drug effects) Gene Expression Regulation, Neoplastic (drug effects) Glioma (drug therapy, enzymology, genetics) Humans Interferon-beta (administration & dosage, pharmacology) O(6)-Methylguanine-DNA Methyltransferase (biosynthesis, genetics) Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction Temozolomide Tumor Suppressor Protein p53 (physiology)

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