TY - JOUR
T1 - Eradication of therapy-resistant human prostate tumors using a cancer terminator virus
AU - Sarkar, Devanand
AU - Lebedeva, Irina V.
AU - Su, Zao Zhong
AU - Park, Eun Sook
AU - Chatman, Lejuan
AU - Vozhilla, Nicollaq
AU - Dent, Paul
AU - Curiel, David T.
AU - Fisher, Paul B.
PY - 2007/6/1
Y1 - 2007/6/1
N2 - Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-xL. 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-xL 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-xL-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEGE1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-xL 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.
AB - Terminal prostate cancer is refractory to conventional anticancer treatments because of frequent overexpression of antiapoptotic proteins Bcl-2 and/or Bcl-xL. 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-xL 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-xL-overexpressing prostate cancer cells confirmed cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEGE1A-mda-7 (CTV) into xenografts derived from DU-145-Bcl-xL 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.
UR - https://www.scopus.com/pages/publications/34347216741
U2 - 10.1158/0008-5472.CAN-07-0195
DO - 10.1158/0008-5472.CAN-07-0195
M3 - Article
C2 - 17545625
AN - SCOPUS:34347216741
SN - 0008-5472
VL - 67
SP - 5434
EP - 5442
JO - Cancer research
JF - Cancer research
IS - 11
ER -