Marshall Digital Scholar

Title

Eradication of Therapy-resistant Human Prostate Tumors Using an Ultrasound-guided Site-specific Cancer Terminator Virus Delivery Approach

Authors

Adelaide Greco
Altomare Di Benedetto
Candace M. Howard
Sarah Kelly
Rounak Nande
Yulia Dementieva
Michele Miranda
Arturo Brunetti
Marco Salvatore
Luigi Claudio
Devanand Sarkar
Paul Dent
David T. Curiel
Paul B. Fisher
Pier P. Claudio, Marshall UniversityFollow

Document Type

Article

Publication Date

2-2010

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.

Comments

This article first appeared in the Feb. 2010 issue of Molecular Therapy, the member magazine of the American Society of Gene & Cell Therapy, and is reprinted with permission. http://www.nature.com/mt/journal/v18/n2/pdf/mt2009252a.pdf

© 2012 American Society of Gene & Cell Therapy

Recommended Citation

Greco A., Di Benedetto A., Howard C.M., Kelly S., Nande R., Dementieva Y., Miranda M., Brunetti A., Salvatore M., Claudio L. Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. Mol. Ther. 2010;18:295–306.