It is well known that androgen deprivation is the cornerstone of initial therapy for metastatic prostate cancer. Once metastatic prostate cancer progresses in the face of hormonal therapy, it is classified as being androgen independent. Therapeutic options for patients with androgen independent prostate cancer are extremely limited. In particular, cytotoxic chemotherapy has provided minimal benefit. The purpose of this project is to perform translational research to develop new agents, and/or therapeutic maneuvers, that appear to have antitumor activity in prostate cancer. To achieve this goal, we have become extensively involved in the efforts to understand the biology of prostate cancer. Currently, we are attempting to correlate biological variables associated with prostate cancer and response to therapy (e.g., mutated androgen receptor, CAG repeats and microvessel count). The Clinical Pharmacokinetics Section reported the first confirmation of the therapeutic efficacy of flutamide withdrawal, as well as the enhanced activity of simultaneous adrenal suppression. It has been hypothesized that the clinical improvement associated with flutamide is a result of the presence of a mutation within the ligand- binding domain of the androgen receptor. As we and others have reported, the human prostate cancer cell line LNCaP, which expresses such a mutated receptor, is stimulated to grow by hydroxy-flutamide, the active metabolite of flutamide. We believe that the mutation in the ligand-binding domain of the androgen receptor causes these normally antagonistic compounds to behave as androgen agonists. Whether this phenomenon is unique to the LNCaP cell line or is also responsible for the observations made in vivo is unknown. This question is being actively pursued in our section. More recently, we have initiated experiments in an attempt to determine which genes are regulated by the androgen receptor. Clinically we have attempted to develop novel agents that alter the biology of the cancer. Agents which we have clinically evaluated include: suramin, phenylacetate, lovastatin, phenylbutyrate, decitabine, gallium, CAI, and somatuline. Currently, we are assessing thalidomide, ketoconazole plus alendronate, tamoxifen plus vinblastine, and COL-3 in patients with androgen indepedent prostate cancer. - angiogenesis, animal models, pharmacokinetics, pharmacology, prostate cancer, vascular endothelial growth factor, clinical trial, drug development, - Human Subjects & Human Tissues, Fluids, Cells, etc.
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