2003 Fiscal Year Final Research Report Summary
Development of a Potent Inhibitor of Metastasis Based on a Cyclic Lysophosphatidic Acid
| Project/Area Number |
13557212
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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 | 展開研究 |
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| Research Field |
医薬分子機能学
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
KOBAYASHI Susumu Tokyo University of Science, Faculty of Pharmaceutical, Professor, 薬学部, 教授 (70101102)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIRO Hiromi Tokyo University of Science, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (00307711)
MUROFUSHI Kimiko Ochanomizu University, Faculty of Science, Professor, 理学部, 教授 (00103557)
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| Project Period (FY) |
2001 – 2003
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| Keywords | Metastasis / Tumor cell invasion / phospholipid / Cyclic phosphatidic acid / Phosphatidic acid / Lysophosphatidic acid |
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| Research Abstract |
Cyclic phosphatidic acid (1-acyl-sn-glycero-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In sharp contrast to LPA, a potent inducer of tumor cell invasion, we previously discovered that palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. Cyclic phosphate is not a stable molecule. It might be hydrolyzed either by chemically or enzymatically. In this regard, we have observed that LPA and cPA are enzymatically produced from phosphatidyl choline by phospholipase D (PLD). It is quite important to design a novel molecule of cPA origin which resists to hydrolysis because resulting hydrolyzed product, LPA is known to induce metastasis. In order to prevent the conversion of cPL to LPA, we carried out a modification on cyclic phosphate moiety. One of the molecules which we designed is a carba analog. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group either at the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM! tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural Pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of Pho activation and was not due to the inhibition or the activation of LPA receptors.
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[Journal Article] Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid2007
Author(s)
A.Uchiyama, M.Mukai, Y.Fujiwara, S.Kobayashi, N.Kawai, H.Murofushi, M.Inoue, S.Enoki, Y.Tanaka, T.Niki, T.Kobayashi, G.Tigyi, K.Murakami-Murofushi
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Journal Title
Biochimica et Biopysica Acta 1771
Pages: 103-112
Description
「研究成果報告書概要(欧文)」より
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