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. [Cancer Res 2007;67(11):5434–42]