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Antitumor Activity of an Oncolytic Adenovirus-Delivered Oncogene Small Interfering RNA

¹ The Mary Crowley Medical Research Center and the ² Cancer Immunology Research Laboratory, Baylor-Sammons Cancer Center, ³ Murex Pharmaceuticals, Dallas, Texas; and ⁴ Institute of Biomedical Studies, Baylor University, Waco, Texas

Requests for reprints: Alex W. Tong, Cancer Immunology Research Laboratory, Baylor Sammons Cancer Center, 530 Sammons Tower, 3500 Gaston Avenue, Dallas, TX 75246. Phone: 214-820-4123; Fax: 214-820-2780; E-mail: alext{at}baylorhealth.edu.

Despite successes in animal models, cancer gene therapy with small interfering RNAs (siRNA) is hindered by the lack of an optimal delivery platform. We examined the applicability of the replication-competent, oncolytic adenovirus, ONYX-411, to deliver a mutant K-ras siRNA transgene to human cancer cells. Proof-of-principle studies showed an additive tumor growth–inhibitory response through siRNA-mediated K-ras knockdown and ONYX-411-mediated cancer cell lysis. A novel construct, termed Internavec (for interfering RNA vector), was generated by cloning a K-ras^v12-specific siRNA^ras-4 hairpin construct under the control of the human H1 promoter into the deleted E3b region of ONYX-411. Internavec acquired an increase in potency of 10-fold in human cancer cells expressing the relevant K-ras^v12 mutation (H79, H441, and SW480), as defined by a reduction in the effective dose needed to achieve 50% growth inhibition (ED₅₀). Internavec remained attenuated in nonmalignant epithelial cells. Daily intratumoral injections of Internavec (five daily injections of 1 x 10⁸ plaque-forming units) significantly reduced the growth of s.c. H79 pancreatic cancer xenografts in nu/nu mice by 85.5%, including complete growth suppression in three of five mice. Parental ONYX-411 or ONYX-411-siRNA^GFP was markedly less effective (47.8% growth reduction, P = 0.03; and 44.1% growth reduction, P = 0.03, respectively). siRNA^ras transgene activity contributed to cell cycle blockage, increased apoptosis, and marked down-regulation of Ras signaling–related gene expression (AKT2, GSK3ß, E2F2, and MAP4K5). These findings indicate that Internavec can generate a two-pronged attack on tumor cells through oncogene knockdown and viral oncolysis, resulting in a significantly enhanced antitumor outcome. (Cancer Res 2006; 66(19): 9736-43)

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