2009 Fiscal Year Final Research Report
Design of Nucleosides Antitumor Agents
| Project/Area Number |
17016001
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Hokkaido University |
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Principal Investigator |
MATSUDA Akira Hokkaido University, 大学院・薬学研究院, 教授 (90157313)
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| Project Period (FY) |
2005 – 2009
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| Keywords | 代謝拮抗剤 / Ecyd / RNAポリメラーゼ / CNDAC / DNAポリメラーゼ / DNA鎖切断 / G2アレスト / アポトーシス |
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| Research Abstract |
We have been developing nucleoside antimetabolites CNDAC and ECyd as new types of antitumor agents. After incorporation of CNDAC in DNA-strands, strand-breaks were induced. In order to repair the breaks, G2-check point was activated. Therefore, it is important to develop its abrogators for combination therapy. We designed a new Chk1 inhibitor, PGED (IC50=2.8nM), which has combination effects with SN-38. ECyd is a potent inhibitor of RNA polymerase after its conversion to the corresponding 5'-triphosphate. In combination treatment with X-ray irradiation and ECyd, antitumor effects towards colon 26 tumors in vivo were effectively enhanced, due to inhibition of expression of antiapoptotic protein such as survivin. We also found that by increasing the length of the bridging linker, the PU3 (an Hsp90 inhibitor) dimmers became more cytotoxic against human breast cancer cell lines.
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[Journal Article] Role of RNase L in apoptosis induced by ECyd.2009
Author(s)
T.Naito, T.Yokogawa, S.Takatori, K.Goda, A.Hiranoto, A.Sato, Y.Kitade, T.Sasaki, A.M atsuda, M.Fukushima, Y.Wataya, H-S.Kim.
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Journal Title
Cancer Chemothr.Pharmacol 63
Pages: 837-50
Peer Reviewed
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