Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach.
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.
Greco
Adelaide
A
Department of Biochemistry and Microbiology, Joan C Edwards School of Medicine, Marshall University, Huntington, West Virginia 25755, USA.
Di Benedetto
Altomare
A
Howard
Candace M
CM
Kelly
Sarah
S
Nande
Rounak
R
Dementieva
Yulia
Y
Miranda
Michele
M
Brunetti
Arturo
A
Salvatore
Marco
M
Claudio
Luigi
L
Sarkar
Devanand
D
Dent
Paul
P
Curiel
David T
DT
Fisher
Paul B
PB
Claudio
Pier P
PP
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
D007378:Interleukins; D000099180:Interleukin-24