1998 Fiscal Year Final Research Report Summary
Gene therapy for malignant brain tumors via TIMPs-expressing replication-competent viruse
| Project/Area Number |
08671614
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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 |
YAZAKI Takahito Keio University School of Medicine Professor, 医学部, 専任講師 (80200484)
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| Co-Investigator(Kenkyū-buntansha) |
HOSHI Michio Keio University School of Medicine Instructor, 医学部, 助手 (00265844)
SASAKI Hikaru Keio University School of Medicine Instructor, 医学部, 助手 (70245512)
UYEMURA Keiichi Keio University School of Medicine Professor, 医学部, 教授 (90049792)
KAWASE Takeshi Keio University School of Medicine Assistant Professor, 医学部, 教授 (40095592)
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| Project Period (FY) |
1996 – 1998
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| Keywords | Brain tumors / Herpes simplex virus / in vasion / gene therapy / virus therapy |
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| Research Abstract |
We have investigated a combined gene therapy to express several functional genes from a suitable vector system. The strategy behind the use of replication-competent, cytotoxic viral vectors is that after infection of a tumor cell the viral vector replicates and kills the infected cell, producing multiple infectious progeny that then infects additional tumor cells and this replication cycle is repeated until the viral infection reaches normal tissue. At first we have generated multiple mutant HSV-G 207 which has deletions of both copies of the 1CP34.5 gene and a lacZ insertion inactivating the ICP6 gene. In vitro, G207 was able to replicate in and destroyed a large number of tumor cell lines. In athymic mice harboring subcutaneous or intracranial human malignant brain tumor cells, G207 infection caused significantly decreased tumor growth and/or prolonged survival. However, for actively invasive malignant tumors, virus replication was not enough to kill most of tumor cells. On the other
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hand, matrix metalloproteinase (MMP) 2 and 9 are strongly expressed in malignant glioma cells and they should dissolve extra cellular matrix (ECM) molecules to get invasion. Tissue inhibitor of metalloptoreinase type 2 (TLMP2) is a physiological inhibitor of MMP2 and 9, and should decrease invasive activity of malignant tumor cells. To strengthen therapeutic strategy of replication-competent HSV therapy, we have generated defective HSV vector expressing TIMP2 by insertion of TIMP2 cDNA into HSV-amplicon plasmid using HSV-G207 as a helper virus. Theoretically this virus should replicate in tumor cells and synchronously secrete TIMP2 into surrounding tissue. In fact, after infection of this virus, we observed that glioma cells decreased their activity of mitosis and invasion both in vitro and in vivo. This newly developed HSV vector increased tumor killing ability comparing with G207. This type of combined gene therapy strategy using single vector system may be an appropriate approach for treating malignant tumors. Less
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