| Project/Area Number |
18310143
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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 |
Living organism molecular science
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| Research Institution | Tokyo University of Agriculture and Technology |
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Principal Investigator |
HASUMI Keiji Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Professor (20208474)
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| Co-Investigator(Kenkyū-buntansha) |
YAGASAKI Kazumi Tokyo University ofAgriculture and Technology, Institute ofSymbiotic Science and Technology, Professor (20166474)
MITSUMORI Kunitoshi Tokyo University ofAgriculture and Technology, Institute of Symbiotic Science and Technology, Professor (10239296)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,460,000 (Direct Cost: ¥16,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥12,000,000 (Direct Cost: ¥12,000,000)
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| Keywords | Bioactive compound / Pharmacological activity / Proteolysis / Angiogenesis / Cancer / Plasminogen / 慢性肝障害 |
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| Research Abstract |
1. Discovery of New SMTP Congeners with Distinguished Activity
The structure of SMTP family plasminogen modulators consist of two molecular parts: one is the triprenyl phenol unit and the other is the N-linked side chain moiety. The fungus Stachybotrys microspora, a producer of SMTP, incorporate an amine compound in the culture medium into the SMTP molecule as the N-linked side chain. Therefore, specific SMTP compound can be selectively produced by adding an appropriate amine compound. By using this method, we isolated 34 new congeners. The congeners were characterized on the basis of plasminogen activation and plasmin fragment formation, and 6 congeners with distinguished activity were further characterized on the basis of plasminogen-fibrin binding and fibrinolysis. Accordingly, the congeners were divided into three groups: (i) compounds with profound activity to enhance proteolysis, (ii) compounds with profound activity to enhance plasmin fragment formation, and (iii) compounds with both activities.
2. Mechanism of the SMTP activity under Physiological Conditions
SMTP-7, a congeners having ornithine as an N-linked side chain, has an activity to enhance both proteolysis and plasmin fragment formation. We explored the mechanism of this compound in the antitumor activity. In an in vivo model using tumor-bearing mice, (i) plasma SMTP level reached a peak after 1 h of intraperitoneal injection, and the acceleration of plasmin formation followed this peak. (ii) Two hours after the SMTP-7 injection, antiangiogenic plasmin fragment level increased in the tumor. (iii) SMTP-7 inhibits tumor-induced angiogenesis in viva (iv) The growth of the implanted tumor was inhibited by the drug at a dose same as that induces plasmin fragment formation and inhibits tumor-derived angiogenesis.
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