2003 Fiscal Year Final Research Report Summary
Gene therapy for oral squamous cell carcinoma with herpes simplex virus vector
| Project/Area Number |
13470432
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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 | 一般 |
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| Research Field |
Surgical dentistry
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| Research Institution | Osaka University |
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Principal Investigator |
YURA Yoshiaki Osaka University, Graduate school of Dentistry, Professor, 大学院・歯学研究科, 教授 (00136277)
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| Co-Investigator(Kenkyū-buntansha) |
SUMI Testuro Osaka University, Dental Hospital, Assistant Professor, 歯学部附属病院, 講師 (40252697)
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| Project Period (FY) |
2001 – 2003
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| Keywords | gene therapy / oral cancer / herpes simplex virus / mutant virus / HMBA / calponin / malignant histiocytoma |
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| Research Abstract |
Oncolytic herpes simplex virus (RSV) therapy with replication-competent HSV type 1(HSV-1) mutant is a promising approach for the treatment of oral cancer, because replication of HSV-1 within cancer cells can result in their destruction. For the treatment of cancer in the oral cavity, it is essential to determine how oral environmental factors could affect the replication of HSV-1 vector. We examined the effect of a calcium ionophore, ionomycin, and oxygen radicals and found that ionomycin increased entracellular virus, whereas it did not change the virus production. Furthermore, H2O2 elevated the level of intracellular calcium ([Ca2+]i) and then increased the extracellular HSV-1, suggesting that [Ca2+]i plays an important role in the release of HSV-1 vector. To eradicate solid tumor, HSV-1 vector must spread from inoculated site to neighboring tumor cells. A polar compound, hexamethylene bisacatamide (HMBA) was found to enhance the replication of γ34.5 mutant R849 in human oral squamous cell carcinoma (SCC) cells. This indicated that HMBA can potentiate the oncolytic effect of R849 on human oral SCC. Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in adult. Nearly 70% of primary human MFH express calponin at various levels, The replication of a HSV-1 mutant d12 CALP in which calponin promoter derives expression of ICP4 was examined in oral MPH cells, Cytopathic effect of d12 CALP was demonstrated in oral MFH that expressed calponin. When nude mice xenografts of MFH were injected with the d12 CALP, a significant reduction of the tumor growth was observed. Furthermore, intravenous administration of the vector resulted in the replication of d12 CALP in lung metastatic lesions. This vector could be usedd for the treatment of distant metastasis of MFH.
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