Enhanced therapeutic efficacy of oncolytic herpes vector G207 against human non-small cell lung cancer-expression of an RNA-binding protein, Musashi1, as a marker for the tailored gene therapy

• Published in: The journal of gene medicine Vol. 8; no. 11; pp. 1329 - 1340
• Main Authors: Kanai, Ryuichi, Eguchi, Keisuke, Takahashi, Miwa, Goldman, Steven, Okano, Hideyuki, Kawase, Takeshi, Yazaki, Takahito
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2006; Wiley Periodicals Inc
• Subjects: Animals; Base Sequence; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - therapy; Cell Line, Tumor; Female; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Mice; Mice, Nude; Musashi1; Neoplasm Transplantation; Nerve Tissue Proteins - genetics; non-small cell lung cancer; oncolytic herpes virus vector G207; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Promoter Regions, Genetic; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; RNA-Binding Proteins - genetics; Transplantation, Heterologous; γ34.5 gene
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.965

Background Oncolytic herpes vectors like G207 have shown considerable promise in the treatment of solid tumors, but their potency must be enhanced for the full achievement of therapeutic efficacy. Deletion of the innate γ34.5 gene made these vectors extremely safe, but their efficacy was also severely attenuated. Use of tumor‐specific promoters is one method to direct toxicity and enhance efficacy against tumors. Recently, Musashi1 has been shown expressed in some tumor tissues. Methods Eleven human cancer cell lines including five non‐small cell lung cancers (NSCLCs) were investigated. Musashi1 mRNA expression was examined by RT‐PCR analysis. Western blotting was also performed. Transcriptional activity of P/musashi1 in NSCLCs was assayed by GFP reporter plasmids. Then we constructed a defective amplicon vector containing musashi1 promoter/ICP34.5 with G207 as helper virus (dvM345). In vitro cytotoxicity against NSCLCs and growth characteristics of helper virus were examined. A Lu‐99 subcutaneous tumor model was used in an animal study. The tumor volume treated with G207 alone or dvM345 was measured. Results Musashi1 mRNA was detected in four cell lines. Two in five NSCLCs were positive, and P/musashi1 was proved functional within them. Against these cell lines, dvM345 showed enhanced cytotoxicity, and helper viral growth was augmented. A subcutaneous tumor study confirmed the enhanced therapeutic efficacy of G207 by dvM345 without compromising safety. Conclusions These results suggest that Musashi1 might be involved in the development of several carcinomas including NSCLC. In the context of oncolytic herpes vector strategy, the P/musashi1‐ICP34.5 method could be used for the treatment of cancers expressing Musashi1. Copyright © 2006 John Wiley & Sons, Ltd.