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Background: Inhibition of histone deacetylase HDAC was shown to be a promising cancer therapeutic approach due to the fact that such inhibition may induce acetylation in histones and transcriptional reactivation of dormant tumor-suppressor genes. The goal of this study is to evaluate the efficacy of a novel, shRNA-based gene therapy approach of HDAC inhibition in combination with radiotherapy.

Methods: A replication-deficient adenovirus encoding a mini shRNA gene targeted to the HDAC gene was engineered and evaluated for its anti-tumor efficacy in combination with radiotherapy in a human colon cancer model. We also used a conditionally replicative adenovirus targeted to telomerase-positive tumor cells for the enhancement of HDAC specific shRNA expression.

Results: The adenovirus (AdsiHDAC) showed significant efficacy in down-regulating the levels of the HDAC protein. Infection of colon cancer cell line HCT116 with AdsiHDAC resulted in much higher apoptosis fraction than control cells infected with a non-targeted virus. The apoptosis involved the caspase 9-caspes 3 pathway. However, when the virus delivered intratumorally to xenograft human tumors, minimal anti-tumor effects of the virus was seen either alone or in combination with radiation therapy, suggesting inefficiency of the non-replicative adenovirus in delivering shRNA genes to the tumor mass. When a conditionally replicative adenovirus targeted to telomerase-positive tumor cells was used in conjunction with the HDAC-targeted shRNA-encoding non-replicative adenovirus, the efficiency of tumor-specific anti-HDAC siRNA gene expression was enhanced significantly. Most importantly, this enhanced siRNA expression led to significant anti-tumor efficacy of concurrently delivered radiation therapy.Conclusion: These results suggest that the shRNA-based HDAC-targeting approach in combination with tumor-targeting replicative adenovirus is a promising approach to sensitize colon cancer cells to radiation therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA