Novel therapeutic strategies in development for prostate cancer.
ABSTRACT Relatively few therapy options exist for patients with prostate cancer that has become resistant to androgen-deprivation therapy and has metastasized to distant sites. Survival for such patients is poor with a median survival of approximately 20 months from the time of initiation of standard docetaxel-based chemotherapy. Promising new treatments are needed, and several are currently being evaluated, including those that target the hormonal axis, such as abiraterone, chemotherapies, such as satraplatin and ixabepilone, combinations of chemotherapy with other agents, such as bevacizumab and calcitriol, as well as a variety of immunotherapeutic approaches. This review will highlight recent and current studies for many of the promising developments for advanced disease, as well as novel early stage approaches.
- SourceAvailable from: tua.org.tw
- [Show abstract] [Hide abstract]
ABSTRACT: In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.Steroids 06/2011; 76(12):1268-79. · 2.72 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The bioactive form of vitamin D, 1,25-dihydroxyvitamin D(3), is a secosteroid hormone that binds to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily, and modulates a variety of biological functions. The VDR is expressed by most cell types, including cells of the urogenital system, such as prostate and bladder cells. In particular, the prostate is a target organ of VDR agonists and represents an extrarenal synthesis site of 1,25-dihydroxyvitamin D(3). We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic component responsible for urinary irritative symptoms, and an inflammatory component. Data reviewed here demonstrate that VDR agonists, and notably elocalcitol, reduce the static component of BPH by inhibiting the activity of intraprostatic growth factors downstream of the androgen receptor, the dynamic component by targeting the RhoA/ROCK pathway in prostate and bladder cells, and the inflammatory component by targeting the NF-kappaB pathway.Annals of the New York Academy of Sciences 04/2010; 1193:146-52. · 4.38 Impact Factor