Exploiting stromal-epithelial interaction for model development and new strategies of gene therapy for prostate cancer and osteosarcoma metastases (review)

摘要

Results of toxic gene therapy for the treatment of localized and disseminated prostate cancers showed that: (i) Ad-OC-TK expressed high levels of TK in both androgen-dependent and androgen-independent human prostate cancer cell lines; (ii) in parallel with the expression of Ad- OC-TK in tumor cell lines, the efficacy of Ad-OC-TK toxic gene therapy in target cells is directly correlated with the levels of TK expression in vitro; (iii) in two experimental models of human prostate cancer, C4-2 and PC-3, we demonstrated that Ad-OC-TK, when applied together with ACV, induced tumoricidal effects in vivo. Significant histomorphologic improvement of human prostate cancer growth in the bone was supported by bone scans in vivo. In the C4-2 model, we obtained evidence that Ad-OC-TK plus ACV diminished serum PSA, which is confirmed by the improvement of histomorphologic appearance of this tumor in the skeleton. Finally, we have focused our effort in the development of combined adenovirus and chemotherapy (i.e. chemogene therapy), the development of a concept of loco-regional delivery of therapeutic genes and drugs, and the exploration of using the homing mechanism to treat prostate cancer skeletal metastasis in vivo. Taking advantage of the reciprocal cellular interaction between prostate cancer and bone stroma, we have developed two novel gene therapy approaches to target prostate cancer growth in the bone.We have achieved for the first time the use of Ad-OC-TK/ACV as a novel therapeutic agent that can selectively target and induce the killing of both prostate and osteoblast lineage cells.