Journal
CANCER RESEARCH
Volume 66, Issue 19, Pages 9736-9743Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-1617
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Funding
- NCI NIH HHS [CA108039] Funding Source: Medline
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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 HI promoter into the deleted E3b region of ONYX-411. Internavec acquired an increase in potency of similar to 10-fold in human cancer cells expressing the relevant K-ras 12 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 10(8) 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, GSK3 beta, 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.
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