Enhanced Gene Transfer and Oncolysis of Head and Neck Cancer and Melanoma Cells by Fiber Chimeric Oncolytic Adenoviruses

• Published in: Clinical cancer research 2006-05, Vol.12 (9), p.2869-2878
• Main Authors: REDDY, P. Seshidhar, GANESH, Shanthi, MATHIS, De-Chaoyu J. Michael, STEWART, Phoebe L, ZHU, Zheng B, CURIEL, David T
• Format: Article
• Language: English
• Subjects: Adenoviral receptors; Adenoviruses, Human - genetics; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Chimera; Dermatology; DNA Primers; Fiber chimeric adenovirus; Gene Transfer Techniques; Genetic Markers; Head and Neck cancer; Head and Neck Neoplasms - therapy; Humans; Medical sciences; Melanoma; Melanoma - therapy; Oncolytic adenovirus; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Polymerase Chain Reaction; Transduction, Genetic; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2397

Purpose: The purpose of this study was to evaluate a fiber knob replacement strategy to improve infectivity and efficacy of Ad5 fiber chimeric oncolytic viruses for treatment of melanoma and head and neck cancers (HNC). Experimental Design: Adenoviral receptors and transduction levels were used to determine the level of infectivity of fiber-modified, green fluorescent protein–expressing, replication-deficient viruses in a panel of melanoma and HNC cell lines in vitro . Virus yield and cytotoxicity assays were used to determine the tumor specificity and virus replication-mediated cytotoxicity of the fiber-modified oncolytic viruses in the same panel of melanoma and HNC in vitro . Xenograft tumor models were used to assess the antitumor activity of those fiber-modified chimeric viruses compared with the parental virus. Results: Marker gene expression following gene transfer of the fiber chimeric vectors in melanoma and HNC cell lines was ∼10-fold higher than that obtained with parental Ad5 vector. The fiber chimeric oncolytic variants mediated killing of melanoma and HNC cells that was 2- to 576-fold better than with the parental virus. In addition, fiber chimeric variants produced 2- to 7-fold more progeny virus in tumor cells than the parental virus. Moreover, a high multiplicity of infection was needed for the fiber chimeric viruses to produce cytotoxicity in normal cells. A significantly stronger antitumor response and survival advantage were shown in the tested melanoma and HNC xenograft models following i.t. injections. Conclusions: In vitro and in vivo studies showed the improved transduction, replication, cytotoxicity, antitumor efficacy, and survival advantage in melanoma and HNC tumor models, suggesting a potential use of these oncolytic agents for the treatment of melanoma and HNCs.