title: Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach.
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.
authors.affiliation: Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, USA.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Greco
authors.forename: Altomare
authors.initials: A
authors.lastname: Di Benedetto
authors.forename: Candace M
authors.initials: CM
authors.lastname: Howard
authors.forename: Sarah
authors.initials: S
authors.lastname: Kelly
authors.forename: Rounak
authors.initials: R
authors.lastname: Nande
authors.forename: Yulia
authors.initials: Y
authors.lastname: Dementieva
authors.forename: Michele
authors.initials: M
authors.lastname: Miranda
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
authors.forename: Luigi
authors.initials: L
authors.lastname: Claudio
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Pier P
authors.initials: PP
authors.lastname: Claudio
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007378:Interleukins / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D000099180:Interleukin-24