Eradication of therapy-resistant human prostate tumors using a cancer terminator virus.
Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-x(L). Adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing properties, profoundly inhibits prostate cancer cell growth. However, forced overexpression of Bcl-2 or Bcl-x(L) renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV generates large quantities of MDA-7/IL-24 as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal prostate epithelial cells and parental and Bcl-2- or Bcl-x(L)-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-x(L) cells in athymic nude mice completely eradicated not only primary tumors but also distant tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for advanced prostate cancer patients with metastatic disease.
Sarkar
Devanand
D
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, USA.
Lebedeva
Irina V
IV
Su
Zao-zhong
ZZ
Park
Eun-Sook
ES
Chatman
Lejuan
L
Vozhilla
Nicollaq
N
Dent
Paul
P
Curiel
David T
DT
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy* / Q000821:virology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics; D000099180:Interleukin-24
D017500:Adenovirus E1A Proteins; D000943:Antigens, Differentiation; D007378:Interleukins; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein; D000099180:Interleukin-24; C489287:Ppp1r15a protein, rat