LIGAND-INDEPENDENT ACTIVATION OF THE ANDROGEN RECEPTOR OF PROSTATE CANCER

由于前列腺癌的生长对雄激素敏感，转移性疾病一直采用雄激素戒断疗法治疗。大多数前列腺癌患者最初对激素治疗有反应，但超过一半的患者逐渐产生耐药性。肿瘤从雄激素应答到雄激素无应答的变化机制通常可以通过克隆选择、适应、信号转导的另一途径和AR参与来解释。在不使用抗雄激素治疗的去势治疗的激素难治性前列腺癌患者中，30%的AR高度扩增。LNCaP模型中的AR n端结构域由IL6通过丝裂原活化蛋白激酶（MAPK）和转录单导和激活因子3 （STAT3）激活。以下结果已经公布：p53-Abs可能有助于临床决定是否进行前列腺活检。血清p53-Abs滴度在总体患者人群和直肠指检正常患者中鉴别前列腺癌和BPD最有用的有效性。预处理血清NSE水平可预测内分泌治疗转移性前列腺癌患者的生存。M1期截瘫患者的生存率与没有瘫痪的M1期患者一样好。这应该鼓励积极的治疗方法。然而，对于激素非依赖性疾病的患者，似乎没有有效的治疗方法，预后较差。显著抑制血清IL-6可能是通过抑制雄激素非依赖性雄激素受体的激活，这可能是地塞米松治疗进展性前列腺癌患者的作用机制之一。已经克隆了AR和转录复合体之间的几个辅助因子，报告表明SRC1与前列腺癌激素难治性进展相关。

Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by androgen withdrawal therapy. Most prostate cancer patients initially respond to hormonal therapy, but over half of them gradually develop resistance. The mechanism of the change in tumours from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and AR involvement. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without antiandrogens. The AR N-terminal domain in the LNCaP model is activated by IL6 via mitogen-activated protein kinase (MAPK) and single transducers and activators of transcription 3 (STAT3).The following results are already published;p53-Abs might be helpful in the clinical decision to perform prostate biopsy. The serum p53-Abs titer had the most useful validity in discriminating between prostate cancer and BPD in the overall patient population and in patients with normal digital rectal examination.The pretreatment serum level of NSE can predict survival of metastatic prostate cancer patients treated with endocrine therapy.Stage M1 patients with paraplegia had survival rates as good as stage M1 patients without paralysis. This should encourage an aggressive treatment approach. However, for patients with hormone-independent disease there seems to be no effective treatment and prognosis is poor.Significant suppression of serum IL-6, probably through inhibition of androgen-independent activation of androgen receptor, may be one of the mechanisms for the effect of dexamethasone therapy in prostate cancer patients with progressive disease.Several co-factors between AR and transcriptional complex have been cloned and reports indicate that SRC1 is correlated with the hormone-refractory progression of prostate cancer.