| Project/Area Number |
22890095
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Kyoto University |
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Principal Investigator |
KONDO Natsuko 京都大学, 原子炉実験所, 助教 (00582131)
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| Project Period (FY) |
2010 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
|
| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2011: ¥1,469,000 (Direct Cost: ¥1,130,000、Indirect Cost: ¥339,000)
Fiscal Year 2010: ¥1,391,000 (Direct Cost: ¥1,070,000、Indirect Cost: ¥321,000)
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| Keywords | FANCD1 / テモゾロミド(TMZ) / 塩酸ニムスチン(ACNU) / HomologousRecombination修復経路 / グリオブラストーマ / Homologous Recombination修復経路 / ファンコニ貧血 / DNA修復路 / 悪性グリオーマ |
|---|
| Research Abstract |
Nimustine(ACNU) and temozolomide(TMZ) are DNA alkylating agents which are commonly used in chemotherapy for glioblastomas. ACNU is a DNA cross-linking agent and TMZ is a methylating agent. The therapeutic efficacy of these agents is limited by the development of resistance. In this work, the role of the Fanconi anemia(FA) repair pathway for DNA damage induced by ACNU or TMZ was examined. Cultured mouse embryonic fibroblasts were used : FANCA^<-/->, FANCC^<-/->, FANCA^<-/-> C^<-/->, FANCD2^<-/-> cells and their parental cells, and Chinese hamster ovary and lung fibroblast cells were used : FANCD1/BRCA2mt, FANCG^<-/-> and their parental cells. Cell survival was examined after a 3 h ACNU or TMZ treatment by using colony formation assays. All FA repair pathways were involved in ACNU-induced DNA damage. However, FANCG and FANCD1/BRCA2 played notably important roles in the repair of TMZ-induced DNA damage. The most effective molecular target correlating with cellular sensitivity to both ACNU and TMZ was FANCD1/BRCA2. In addition, it was found that FANCD1/BRCA2 small interference RNA efficiently enhanced cellular sensitivity toward ACNU and TMZ in human glioblastoma A172 cells. These findings suggest that the down-regulation of FANCD1/BRCA2 might be an effective strategy to increase cellular chemo-sensitization towards ACNU and TMZ.
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