| Project/Area Number |
14580611
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | The University of Tokushima |
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Principal Investigator |
NAGASAWA Hideko The University of Tokushima, Faculty of Engineering, Associate Professor, 工学部, 助教授 (90207994)
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| Co-Investigator(Kenkyū-buntansha) |
HORI Hitoshi The University of Tokushima, Faculty of Engineering, Professor, 工学部, 教授 (90119008)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | hypoxic cytotoxin / HIF-1α / angiogenic inhibition / hypoxia / apoptosis / HIF-1α / 低酸素細胞 / HIF-1 / VEGF / がん微小環境 / p53 |
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| Research Abstract |
Background : Hypoxia represents an important tumor-specific target for cancer therapy. We have reported that hypoxic cytotoxins, such as TX-1102, tirapazamine (TPZ) and TX-402, selectively induced tumor cells to p53-independent apoptosis under hypoxic conditions and inhibited angiogenesis.
Method : We investigated the effects of the antiangiogenic hypoxic cytotoxins on hypoxia-induced gene expression and th6ir hypoxia-selective cytotoxicity in human squamous cell carcinoma of the head and neck (SAS cells) and p53-deficient human non-small cell lung carcinoma H1299 cells transfected with either wild-type or mutantp53 gene.
Results : TX-402 had more potent hypoxia-selective cytotoxicity. than TPZ in either cell regardless of p53 status. All the compounds inhibited angiogenesis potently at doses of more than 5 μg/CAM in chick embryo chorioallantoic membrane (CAM) assay. RT-PCR analyses indicated that TX-402 reduced the inducible expression of vascular endothelial cell growth factors (VEGE) and glucose transporter type 3 (GLUT-3) under hypoxic conditions selectively. The mRNA and protein expression of HIF-1α were also suppressed by TX-402 at the same time.
Conclusion : The potent antiangiogenic effects of hypoxic cytotoxins can be attributed to the suppression of VEGF and HIF-1 induction through the hypoxia-inducible pathway. We show an other aspect of the hypoxic cytotoxin as an HIF-1 inhibitor for hypoxia-targeted therapy to improve cancer treatment and prognosis.
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