2011 Fiscal Year Final Research Report
Development of molecular imaging tracers for anticancer drug resistant proteins
| Project/Area Number |
21390409
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
NATSUME Atsushi 名古屋大学, 大学院・医学系研究科, 准教授 (30362255)
SUZUKI Masaaki 独立行政法人理化学研究所, 分子イメージング科学研究センター, 副センター長 (90093046)
KOYAMA Hiroko 岐阜大学, 大学院・医学系研究科, 助教 (50402160)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 分子イメージング |
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| Research Abstract |
The DNA repair protein O6-methylguanine-DNA methyltransferase(MGMT, AGT) is a determinant of the resistance of tumor cells to alkylating anticancer agents that target the O6 position of guanine. MGMT promoter methylation in tumors is regarded as the most common predictor of the responsiveness of glioblastoma to alkylating agents. However, MGMT promoter methylation status has been investigated mainly by methylation-specific PCR(MSP), which is a qualitative and subjective assay. In addition, the actual enzymatic activities associated with the methylation status of MGMT have not been explored. In the present study, we aimed to create a novel non-invasive MGMT imaging rather than MSP. First, we performed bisulfite pyrosequencing, and its correlation with enzymatic activity was determined using a novel quantitative assay for studying the functional activity of MGMT. MGMT enzymatic activity was assessed using fluorometrically labeled oligonucleotide substrates containing MGMT-specific DNA lesions and capillary electrophoresis to detect and quantify these lesions. In comparison with existing traditional assays, this assay was equally sensitive but less time consuming and easier to perform. MGMT promoter methylation was assessed in 41 glioblastomas by bisulfite pyrosequencing, and 5 samples with different values were chosen for comparison with enzymatic assays. In comparative studies, MGMT promoter methylation values obtained by bisulfite pyrosequencing were inversely proportional to the measured enzymatic activity. The present results indicate that the quantification of MGMT methylation by bisulfite pyrosequencing represents its enzymatic activity and thus, its therapeutic responsiveness to alkylating agents.
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[Journal Article] A multicenter phase I trial of combination therapy with interferon-beta and temozolomide for high-grade gliomas(INTEGRA study) the final report2011
Author(s)
Wakabayashi T, Kayama T, Nishikawa R, Takahashi H, Hoshimoto N, TakahashiJ, Aoki T, Sugiyama K, Ogura M, Natsume A, Yoshida J.
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Journal Title
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[Journal Article] The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promotor methylation and is a better prognostic factor for glioma2011
Author(s)
Ohka F, Natsume A, Motomura K, KishidaY, Kondo Y, Abe T, Nakasu Y, Namba H, Wakai K, Fukui T, Momota H, Iwami K, Kinjo S, Ito M, Fujii M, Wakabayashi T
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Journal Title
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[Journal Article] Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells2010
Author(s)
T Kato, A Natsume, H Toda, H Iwazumi, T Sugita, R Hachisu, R Watanabe, KYuki, K Motomura, K Bankiewicz, T Wakabayashi
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Journal Title
Gene Therapy
Volume: 17(11)
Pages: 1363-1371
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[Journal Article] Retrovirally engineered T cell-based immunotherapy targeting type-III variant epidermal growth factor receptor, a gloma-associated antigen2010
Author(s)
M Ohno, A Natsume, H Iwamizu, D Ito, Y Toi, K Iwami, K Noritake, M Ito, KMotomura, J Yoshida, K Yoshikawa, T Wakabayashi
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Journal Title
Cancer Scinece
Volume: 101(12)
Pages: 2518-2524
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