Identify SNPs and Polymorphisms that are Important in th

众所周知，雄激素剥夺是转移性前列腺癌初始治疗的基石。一旦转移性前列腺癌在激素治疗下进展，它被归类为雄激素独立。雄激素非依赖型前列腺癌患者的治疗选择非常有限。特别是，细胞毒性化疗提供的益处微乎其微。该项目的目的是进行转化研究，以开发新的药物，和/或治疗方法，似乎在前列腺癌中具有抗肿瘤活性。为了实现这一目标，我们已经广泛参与了解前列腺癌生物学的努力。目前，我们正试图将与前列腺癌和治疗反应相关的生物学变量（例如，突变的雄激素受体、CAG重复序列和微血管计数）联系起来。分子药理学部分报道了氟他胺停药治疗效果的首次证实，以及同时肾上腺抑制活性的增强。据推测，与氟他胺相关的临床改善是雄激素受体的配体结合区域内存在突变的结果。正如我们和其他人报道的那样，表达这种突变受体的人前列腺癌细胞LNCaP在氟他胺的活性代谢物羟基氟他胺的刺激下生长。我们认为雄激素受体配体结合区域的突变导致这些通常拮抗的化合物表现为雄激素激动剂。这种现象是LNCaP细胞系所特有的，还是体内观察结果的原因尚不清楚。我们部门正在积极地研究这个问题。最近，我们开始了一项实验，试图确定哪些基因是由雄激素受体调节的。特别是，我们对AR（外显子1的三核苷酸重复- CAG重复）的多态性感兴趣。

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 Molecular Pharmacology Sectionreported 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. In particular, we are interested in a polymorphism in the AR (a trinucleotide repeat in exon 1 -- CAG repeat). We are interested in analyzing several candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. All of the genes listed below have shown preliminary evidence that suggests that they may play important roles. Genes involved in the natural production of endostatin (COL18A1), the enzymes involved in testosterone processing (SRD5A1&2), drug metabolism (CYP3A4 &5), and genes involved in cellular transport and conjugation (UGT1A1, UGT2B15, UGT2B17) are being investigated for their involvement in the onset, progression and metastasis of prostate cancer.