| Project/Area Number |
13671464
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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 |
Cerebral neurosurgery
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| Research Institution | Keio University |
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Principal Investigator |
KAWASE Takeshi (2002) Keio University, School of Medicine, Professor, 医学部, 教授 (40095592)
池田 圭朗 (2001) 慶應義塾大学, 医学部, 助手 (10222879)
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| Co-Investigator(Kenkyū-buntansha) |
SHINODA Atsuo Keio University, School of Medicine, Instructor, 医学部, 助手 (60306719)
YAZAKI Takahito Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (80200484)
河瀬 斌 慶應義塾大学, 医学部, 教授 (40095592)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Brain Tumor / herpes simplex virus / γ34.5 / Musashi promoter / Anti-virus immuology / 脳腫瘍 |
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| Research Abstract |
G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both g34.5 loci and a lacZ insertion disabling the U_L39 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of the phase I trial, however, though G207 was proved to be safe, the efficacy was not so impressive. Deletion of the g34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV type1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we reintroduced the g34.5 gene into G207 in the form of a defective vector (dvM345) under transcriptional control of the Musashi1 promoter (P/musashi1). Musashi1, an evolutionarily conserved neural RNA-binding protein, has recently been shown to be expressed in human malignant gliomas and can be used as a marker for them. The expression level of Musashi1 is known to well correlate with the malignancy of the gliomas. Here, we fond that its promoter, P/musashi1 was shown to function selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, compared to G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of g34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype of G207.
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