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.
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 gamma34.5 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.
Kanai
Ryuichi
R
Molecular Neurosurgery Laboratory, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Eguchi
Keisuke
K
Takahashi
Miwa
M
Goldman
Steven
S
Okano
Hideyuki
H
Kawase
Takeshi
T
Yazaki
Takahito
T
D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins