1. ¹Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
2. ²Department of Biomorphological and Functional Science, University of Naples "Federico II", Naples, Italy
3. ³IRCCS SDN Foundation, Naples, Italy
4. ⁴CEINGE-Advanced Biotechnology, s.c.ar.l., Naples, Italy
5. ⁵Department of Basic and Applied Biology, Faculty of Sciences, University of L'Aquila, L'Aquila, Italy
6. ⁶Department of Orthopedic Surgery, Marshall University, Huntington, West Virginia, USA
7. ⁷Department of Mathematics, Marshall University, Huntington, West Virginia, USA
8. ⁸Urology Department, National Cancer Institute "Fondazione Senatore Pascale", Naples, Italy
9. ⁹Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
10. ¹⁰Department of Biochemistry and Molecular Biology, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
11. ¹¹Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
12. ¹²Division of Human Gene Therapy, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
13. ¹³Division of Human Gene Therapy, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
14. ¹⁴Division of Human Gene Therapy, the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
15. ¹⁵Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA

Correspondence: Pier Paolo Claudio, Department of Biochemistry and Microbiology, Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, USA. E-mail: claudiop@marshall.edu

Received 16 March 2009; Accepted 7 October 2009; Published online 3 November 2009.

Abstract

Intratumoral injections of a replication-incompetent adenovirus (Ad) expressing melanoma differentiation–associated gene-7/interleukin-24 (Ad.mda-7), a secreted cytokine displaying cancer-selective, apoptosis-inducing properties, profoundly inhibits prostate cancer (PC) growth in immune-incompetent animals. In contrast, Ad.mda-7 is ineffective in PCs overexpressing antiapoptotic proteins such as Bcl-2 or Bcl-x_L. However, intratumoral injections of a conditionally replication-competent Ad (CRCA) in which expression of the adenoviral E1A gene is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/interleukin (IL)-24 in the E3 region of the Ad (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV), is highly active in these cells. A major challenge for gene therapy is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles—MBs) are viable candidates for gene delivery/therapy. Here, we show that MB/Ad.mda-7 complexes targeted to DU-145 cells using US dramatically reduced tumor burden in xenografted nude mice. Additionally, US-guided MB/CTV delivery completely eradicated not only targeted DU-145/Bcl-x_L-therapy-resistant tumors, but also nontargeted distant tumors (established in the opposite flank), thereby implementing a cure. These findings highlight potential therapeutic applications of this novel image-guided gene therapy technology for advanced PC patients with metastatic disease.