| Project/Area Number |
14370505
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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 |
Urology
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| Research Institution | Graduate School Tokyo Medical and Dental University |
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Principal Investigator |
KAGEYAMA Yukio Tokyo Medical and Dental Univ., Department of Urology, Associate professor, 大学院・医歯学総合研究科, 助教授 (10211153)
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| Co-Investigator(Kenkyū-buntansha) |
SUGIYAMA Hiroshi Kyoto Univ., Department of Chemistry, Professor, 大学院・理学研究科, 教授 (50183843)
KIHARA Kazunori Tokyo Medical and Dental Univ., Department of Urology, Professor, 大学院・医歯学総合研究科, 教授 (40161541)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | Polyamide / Renal cell cancer / Hypoxia inducible factor / VEGF / Neovascularization / 低酸素 / 転写因子 / 血管内皮成長因子 / 低酸素応答転写因子 / HRE / 血管新生抑制 / ピロールイミダゾールポリアミド / 腎癌 |
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| Research Abstract |
Hypoxia inducible factor (HIF), a master regulator of critical genes for cell survival under hypoxia, is known to be related to tumorigenesis and progression of renal cell carcinoma. N-methylpyrrole (Py)-N-methylimidazole (Im) hairpin polyamides are synthetic organic compounds which recognize and bd to minor groove of specific DNA sequences. We synthesized three Py-Im hairpin polyamides targeting the flanking sequences of hypoxia responsive element (a binding site of HIF) in the promoter region of the vascular endothelial growth factor (VEGF) gene. Effects of the polyamides on HIF-induced transcription was evaluated by luciferase assay using a reporter plasmid containing VEGF promoter. Real time reverse transcriptase polymerase chain reaction and enzyme-linked immunosolvent assay were performed to examine effects of the polyamides on transcription and secretion of VEGF in A498 renal cell carcinoma cells which has a frame shift mutation in the von Hippel-Lindau gene. Combinations of three Py-Im hairpin polyamides suppressed HIF-induced transcription in reporter assays using 293 cells, and successfully suppressed transcription and translation of the VEGF gene in A498 cells. The approach using Py-Im hairpin polyamides may provide a new strategy for the treatment of renal cell carcinoma that is resistant to conventional chemotherapy or irradiation.
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