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J Natl Cancer Inst ; 98(21): 1546-57, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17077357

RESUMO

BACKGROUND: An ideal virus for the treatment of cancer should have effective delivery into multiple sites within the tumor, evade immune responses, produce rapid viral replication, spread within the tumor, and infect multiple tumors. Vesicular stomatitis virus (VSV) has been shown to be an effective oncolytic virus in a variety of tumor models, and mutations in the matrix (M) protein enhance VSV's effectiveness in animal models. METHODS: We evaluated the susceptibility of 14 glioma cell lines to infection and killing by mutant strain VSV(deltaM51), which contains a single-amino acid deletion in the M protein. We also examined the activity and safety of this strain against the U87 and U118 experimental models of human malignant glioma in nude mice and analyzed the distribution of the virus in the brains of U87 tumor-bearing mice using fluorescence labeling. Finally, we examined the effect of VSV(deltaM51) on 15 primary human gliomas cultured from surgical specimens. All statistical tests were two-sided. RESULTS: All 14 glioma cell lines were susceptible to VSV(deltaM51) infection and killing. Intratumoral administration of VSV(deltaM51) produced marked regression of malignant gliomas in nude mice. When administered systemically, live VSV(deltaM51) virus, as compared with dead virus, statistically significantly prolonged survival of mice with unilateral U87 tumors (median survival: 113 versus 46 days, P = .0001) and bilateral U87 tumors (median survival: 73 versus 46 days, P = .0025). VSV(deltaM51) infected multifocal gliomas, invasive glioma cells that migrated beyond the main glioma, and all 15 primary human gliomas. There was no evidence of toxicity. CONCLUSIONS: Systemically delivered VSV(deltaM51) was an effective and safe oncolytic agent against laboratory models of multifocal and invasive malignant gliomas, the most challenging clinical manifestations of this disease.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/patologia , Glioma/terapia , Terapia Viral Oncolítica/métodos , Proteínas da Matriz Viral/administração & dosagem , Animais , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Corantes Fluorescentes , Regulação Neoplásica da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/tratamento farmacológico , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Proteínas Luminescentes , Camundongos , Camundongos Nus , Proteínas Recombinantes/administração & dosagem , Projetos de Pesquisa , Infecções por Rhabdoviridae/virologia , Transfecção , Células Tumorais Cultivadas , Proteínas da Matriz Viral/genética , Proteína Vermelha Fluorescente
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