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1.
Gene Ther ; 11(23): 1694-702, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15496964

RESUMEN

Oncolytic adenoviruses constitute a new and promising tool for cancer treatment that has been rapidly translated into clinical trials. However, minimal or absent expression of the adenovirus serotype 5 (Ad5) receptor CAR (coxsackievirus and adenovirus receptor) on cancer cells represents a major limitation for Ad5-based oncolysis. Here, we report on the resistance of CAR-negative primary melanoma cells to cell killing by wild-type Ad5 (Ad5wt) even after high titer infection, thus underlining the need for tropism-modification of oncolytic adenoviruses. We engineered a new generation of oncolytic adenoviruses that exhibit both efficient target cell infection by swapping Ad5 fiber domains with those of Ad serotype 3, which binds to a receptor distinct from CAR, and targeted virus replication. Fiber chimerism resulted in efficient cytopathicity to primary melanoma cells, which was at least 10(4)-fold increased relative to Ad5wt. Since viral infectivity mediated by such modified viral capsids was not cell type-specific, it was pivotal to carefully restrict adenoviral replication to target cells. Towards this end, we replaced both E1A and E4 promoters of fiber chimeric viruses by tyrosinase enhancer/promoter constructs. The resulting viruses showed melanoma-specific expression of E1A and E4 and combined efficient virus replication and cell killing in melanoma cell lines and primary melanoma cells with a remarkable specificity profile that implements strong attenuation in nonmelanoma cells, including normal fibroblasts and keratinocytes.


Asunto(s)
Adenoviridae/fisiología , Melanoma/virología , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Proteínas E4 de Adenovirus/genética , Proteínas E4 de Adenovirus/metabolismo , Proteínas de la Cápside/metabolismo , Muerte Celular , Quimerismo , Proteína de la Membrana Similar al Receptor de Coxsackie y Adenovirus , Efecto Citopatogénico Viral , Humanos , Melanoma/metabolismo , Melanoma/patología , Plásmidos , Regiones Promotoras Genéticas , Receptores Virales , Tropismo , Células Tumorales Cultivadas , Replicación Viral
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