Microbubble-Assisted P53, Rb, And P130 Gene Transfer In Combination With Radiation Therapy In Prostate Cancer.

Direct intratumoral (IT) injections of replication incompetent adenovirus expressing p53 and retinoblastoma family members pRb and p130 inhibit cancer growth in immune incompetent animals. Combination treatment of radiation therapy and direct IT injection of adenoviral vectors has been explored by others to enhance the therapeutic potential of gene transfer. A major challenge for gene transfer is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles) are viable candidates for targeted delivery of genes administered systemically. Here we show that microbubble (MB) p53, pRB, and p130 gene transfer mediated by US at the tumor site resulted in targeted gene transduction and reduction in tumor growth compared to DU-145 prostate cancer cell xenografts treated intratumorally with Ads or radiation alone. Microbubble-assisted/US-mediated Ad.p53 and Ad.RB treated tumors showed considerable greater reduction in tumor volume compared to Ad.p130 treated tumors. Additionally, US mediated microbubble delivery of p53 and RB combined with external beam radiation resulted in the most profound tumor reduction in DU-145 xenografted nude mice (p<0.05). These findings highlight the potential therapeutic applications of this novel image-guided gene transfer technology in combination with external beam radiation for prostate cancer patients with therapy resistant disease.