Viroreplicative Gene Therapy Targeted to Prostate Cancer

摘要

Replication-competent retrovirus (RCR) vectors can propagate specifically within actively dividing cancer cells and achieve highly efficient and tumor-selective gene delivery. To improve their tumor-specificity and safety profile, we have developed RCR vectors regulated by two different tissue- specific promoters. The first is regulated by a synthetic variant of the probasin promoter (ARR2PB), exhibits high specificity for androgen receptor (AR)-positive prostate cancer cells. The second incorporates a newly developed androgen-independent synthetic regulatory element (PSES) which is highly active in PSA-/PSMA-positive prostate cancer cells, both in the presence and absence of androgen. The wild type promoter in the retrovirus long-terminal repeat (LTR) sequence was replaced with ARR2PB and PSES promoter sequences, and the efficiency and specificity of transduction and replication by the resultant RCR vectors was examined in vitro and in vivo. We have also developed prostate- targeted RCR vectors carrying the yeast cytosine deaminase (yCD) gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5- fluorouracil, and the potency and selectivity of the cytotoxic effect mediated by these vectors was examined.