关键词：雄激素；代谢物；前列腺癌；合成（化学）
摘 要：We hypothesized that dehydroepiandrosterone metabolites or their synthetic derivatives are able to bind to the androgen receptor with low, if any, agonist activity and thus function as better antiandrogens than currently available ones. We previously identified three potential compounds with marginal androgenic activity. Using different prostate cancer cell lines, we showed that these compounds could inhibit androgen-induced growth of androgen receptor-positive tumors in vitro. We have then assessed the anti-tumor activities of these compounds in mouse xenograft models for prostate cancer. Inconsistent with our in vitro data, treatment with the dehydroepiandrosterone derivatives even at a relatively high dose resulted in modest decreases in the growth of inoculated tumors as well as the expression of angiogenesisand metastasis-related genes in the tumors. In addition, the compounds did not show significant chemopreventive effects on prostate carcinogenesis in the TRAMP transgenic mouse model. Competitive androgen binding assays revealed that all these compounds were able to compete significantly with androgens for androgen receptor binding. The compounds were also found to inhibit androgen-induced androgen receptor protein expression yet had little influence on the protein stability in prostate cancer cells.