2003 Fiscal Year Final Research Report Summary
Molecular design of nucleoside analogs for selective telomerase inhibition based on mechanisms of action.
| Project/Area Number |
14572102
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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 |
医薬分子機能学
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| Research Institution | Teikyo University of Science & Technology |
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Principal Investigator |
YAMAGUCHI Toyofumi Teikyo University of Science & Technology, Undergraduate School of Science & Engineering, Associate Professor, 理工学部, 助教授 (90230367)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAI Toshiaki Teikyo University of Science & Technology, Instructor, 理工学部, 助手 (30238331)
SANEYOSHI Mineo Teikyo University of Science & Technology, Undergraduate School of Science & Engineering, Professor, 理工学部, 教授 (20002339)
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| Project Period (FY) |
2002 – 2003
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| Keywords | telomere / telomerase / AZddG / AZddGTP / AZT / HL6O cells / antitumor agent / carbocyclic oxetanocin |
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| Research Abstract |
Molecular designing of nucleosides and corresponding 5'-triphosphates as potential selective inhibitor for telomerase has been considered ;
We investigated the inhibitory effects of some sugar-modified nucleotide analogs on human telomerase. Among them, 3'-azido-2',3'-dideoxyguanosin (AZddG) 5'-triphosphate (AZddGTP), carbocyclic oxetanosin G triphosphate (c-oxtGTP) and some guanine-nucleotides showed more potent inhibitory activity against HeLa cell telomerase than that of thymine counterpart (AZTTP). AZddGTP seemed to be able to act as a chain terminator. AZddGTP did not show significant inhibitory activity against vertebrate DNA polymerase α and δ, suggesting that AZddGTP is a selective inhibitor telomerase. Next, we analyzed whether AZddG could alter telomere length and growth rates of human HL6O cells in culture. As the results, long-term treatment of AZddG caused reproducible telomere shortening, and a slight but steady decrease of cell growth rate. Thus, AZddG is an interesting potential telomerase inhibitor. Although telomere-shortening activity of AZddG was not potentiated when combined with arabinofuranosylcytosine (araC) in a preliminary experiment, further study of telomerase inhibitor as potentiators of conventional antitumor agents is now under way.
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