Novel strategy to enhance temozolomide sensitivity with interference of base excision DNA repair system for malignant glioma
| Project/Area Number |
25462277
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurosurgery
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| Research Institution | Kyorin University |
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Principal Investigator |
Nagane Motoo 杏林大学, 医学部, 教授 (60327468)
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| Research Collaborator |
SHIOKAWA Yoshiaki
OKADA Kyoko
SHIMIZU Saki
SUZUKI Kaori
McDONALD Kerrie
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| Project Period (FY) |
2013-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 脳腫瘍 / 神経膠腫 / PARP阻害剤 / テモゾロミド耐性 / 膠芽腫 / temozolomide / 薬剤耐性 / MGMT / ABT888 / temozolomide耐性 |
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| Outline of Final Research Achievements |
Glioblastoma (GBM) is highly malignant and intractable to standard temozolomide (TMZ) treatment. TMZ induces cytotoxic O6-methylguanine lesion in tumor cell DNA, which is repaired by MGMT leading to TMZ resistance. TMZ preferentially induces N7-methylguanine and N3-methylalanine lesions, but they can be repaired through base excision repair system where poly (ADP-ribose) polymerase (PARP) plays a central role. Thus interference with PARP would be expected to conquer TMZ resistance. We treated human GBM cell lines with PARP inhibitors (ABT888) with or without TMZ and found that combination of TMZ plus ABT888 significantly strengthened cell death in GBM cell lines with methylated MGMT but also in those with unmethylated MGMT compared to either treatment alone. This synergistic effect was further observed in GBM cell lines derived from TMZ refractory patients as well as TMZ-resistant subclones. These results suggest the potential clinical usefulness of combining PARP inhibitors to TMZ.
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Report
(4 results)
Research Products
(35 results)
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[Journal Article] Genetic and epigenetic stability of oligodendrogliomas at recurrence.2017
Author(s)
Aihara K, Mukasa A, Nagae G, Nomura M, Yamamoto S, Ueda H, Tatsuno K, Shibahara J, Takahashi M, Momose T, Tanaka S, Takayanagi S, Yanagisawa S, Nejo T, Takahashi S, Omata M, Otani R, Saito K, Narita Y, Nagane M, Nishikawa R, Ueki K, Aburatani H, Saito N
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Journal Title
Acta Neuropathol Commun.
Volume: 5
Issue: 1
Pages: 18-18
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.2016
Author(s)
Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, Tanaka S, Mukasa A, Shirahata M, Shimizu S, Suzuki K, Saito K, Kobayashi K, Higuchi F, Uzuka T, Otani R, Tamura K, Sumita K, Ohno M, Miyakita Y, Kagawa N, Hashimoto N, Hatae R, Yoshimoto K, Shinojima N, Nakamura H, Kanemura Y, Okita Y, et al.
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Journal Title
Acta Neuropathol Commun.
Volume: 4
Issue: 1
Pages: 79-79
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-)2016
Author(s)
Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H, Nagano O.
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Journal Title
Cancer Research
Volume: in press
Issue: 10
Pages: 2954-2963
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Tolerability and pharmacokinetics (PK) of ABT-414 in Japanese patients (pts) with malignant glioma2016
Author(s)
Nagane M, Narita Y, Kagawa N, Mishima K, Yamamoto T, Wakabayashi T, Hamada T, Odagawa R, Nishimura Y, Kiriyama T, Xiong H, Ocampo C, Nishikawa R
Organizer
ESMO ASIA 2016
Place of Presentation
Singapore
Year and Date
2016-12-17
Related Report
Int'l Joint Research
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