SEQUENTIAL/ADDITIVE HORMONAL THERAPY FOR PROSTATE CANCER

尽管在前列腺癌的检测和原发性前列腺癌的治疗方面取得了进展， 转移性前列腺癌仍然是前列腺癌的主要原因。 男性癌症死亡人数虽然转移性疾病通常会 雄激素剥夺，大多数男性获得雄激素非依赖性（AI） 两年内发病。 最近的观察表明， 有时AI疾病仍然对进一步的激素治疗有反应。 这可能是因为雄激素受体（AR）始终 在AI癌症中表达，这意味着前列腺癌细胞可以 可以想象的是，通过该途径保持对刺激的敏感。工作 在这个实验室进行的研究表明，AI疾病有时可以 与AR突变有关。 体外研究 这些突变体的表型显示，抗雄激素比卡鲁胺 是一个有效的对手。根据这些数据，一项临床试验 1995年6月开始使用高剂量比卡鲁胺， 无明显毒性反应。目前的提案寻求 在这一发现的基础上， 氨鲁米特和氢化可的松的时间进展 比卡鲁胺。随着进一步进展，比卡鲁胺将 停药以确定患者是否表现出比卡鲁胺- 戒断反应 正如我们之前的研究一样，这项试验是 一个更大的承诺，包括评估翻译 终点集中于AR的表达和表型， 激素环境后，连续的激素演习。 的 这项试验的总体目标是延长和延长 前列腺癌的激素敏感性，并提高我们的理解 调节雄激素独立性的机制。

Despite advances in prostate cancer detection and treatment of primary disease, metastatic prostate cancer continues to be a leading cause of cancer deaths in men. Although metastatic disease typically responds to androgen deprivation, most men acquire androgen-independent (AI) disease within 2 years. Recent observations have suggested that sometimes AI disease remains responsive to further hormonal therapies. This may be because the androgen receptor (AR) is consistently expressed in AI cancers, implying that prostate cancer cells could conceivably remain sensitive to stimulation via this pathway. Work performed in this laboratory suggested that AI disease can sometimes be associated with AR mutations. Investigation of the in vitro phenotype of these mutants revealed that the antiandrogen bicalutamide was an effective antagonist. Based on these data, a clinical trial begun in June of 1995 using high-dose bicalutamide resulted in a 20% response rate without appreciable toxicity. The current proposal seeks to build on this finding by initiating adrenocortical suppression using aminoglutethimide and hydrocortisone at the time progression on bicalutamide. With further progression, bicalutamide will be discontinued to determine if patients demonstrate a bicalutamide- withdrawal response. As in our previous study, this trial is part of a larger undertaking that includes assessment of translational endpoints focusing on the expression and phenotype of the AR, and the hormonal environment following sequential hormonal maneuvers. The overall goals of this trial are to prolong and extend the period of prostate cancer's hormonal sensitivity and to enhance our understanding of the mechanisms mediating androgen-independence.