Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses.

Otsuki, Akihiro; Patel, Ankita; Kasai, Kazue; Suzuki, Masataka; Kurozumi, Kazuhiko; Chiocca, E Antonio; Saeki, Yoshinaga

Otsuki, Akihiro; Patel, Ankita; Kasai, Kazue; Suzuki, Masataka; Kurozumi, Kazuhiko; Chiocca, E Antonio; Saeki, Yoshinaga.

Afiliación

Otsuki A; Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, 43210 USA.

Mol Ther ; 16(9): 1546-55, 2008 Sep.

Article en En | MEDLINE | ID: mdl-18648350

RESUMEN

Replication-conditional (oncolytic) mutants of herpes simplex virus (HSV), are considered promising therapeutic alternatives for human malignancies, and chemotherapeutic adjuvants are increasingly sought to augment their efficacy. Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agents because of their potent activity in growth arrest, differentiation, and apoptotic death of cancer cells. The ability of the HDAC inhibitors to upregulate exogenous transgene expression and inhibit interferon (IFN) responses prompted our exploration of their use in improving the antitumor efficacy of oncolytic HSV. We discovered that the yield of viral progeny increased significantly when cultured glioma cells were treated with HDAC inhibitors before viral infection. Valproic acid (VPA), a commonly used antiepileptic agent with HDAC inhibitory activity, proved most effective when used to treat glioma cells before viral infection, but not concomitantly with viral infection. Pretreatment with VPA inhibited the induction of several IFN-responsive antiviral genes, augmented the transcriptional level of viral genes, and improved viral propagation, even in the presence of type I IFNs. Moreover, VPA pretreatment improved the propagation and therapeutic efficacy of oncolytic HSV in a human glioma xenograft model in vivo. These findings indicate that HDAC inhibitors can improve the efficacy of tumor virotherapies.

Asunto(s)

Antineoplásicos/uso terapéutico; Inhibidores Enzimáticos/uso terapéutico; Glioma/tratamiento farmacológico; Herpesvirus Humano 1/genética; Inhibidores de Histona Desacetilasas; Interferón beta/uso terapéutico; Virus Oncolíticos; Animales; Neoplasias Encefálicas/genética; Neoplasias Encefálicas/terapia; Neoplasias Encefálicas/virología; Butiratos/uso terapéutico; Sinergismo Farmacológico; Quimioterapia Combinada; Terapia Genética; Vectores Genéticos/uso terapéutico; Glioma/genética; Glioma/virología; Infecciones por Herpesviridae/tratamiento farmacológico; Infecciones por Herpesviridae/genética; Infecciones por Herpesviridae/virología; Herpesvirus Humano 1/metabolismo; Humanos; Interferón beta-1a; Melanoma/tratamiento farmacológico; Melanoma/genética; Melanoma/virología; Ratones; Ratones Desnudos; Proteínas Recombinantes/uso terapéutico; Células Tumorales Cultivadas; Ácido Valproico/uso terapéutico; Replicación Viral/efectos de los fármacos; Ensayos Antitumor por Modelo de Xenoinjerto

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interferón beta / Herpesvirus Humano 1 / Inhibidores Enzimáticos / Virus Oncolíticos / Inhibidores de Histona Desacetilasas / Glioma / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2008 Tipo del documento: Article Pais de publicación: Estados Unidos

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