Targeted Death of Prostatic Cancer Cells

描述(申请人提供)：男性转移性前列腺癌的标准治疗方法是通过双侧切除或黄体生成素释放激素类似物的雄激素消融来缩小肿瘤大小。虽然许多前列腺癌细胞在没有雄激素的情况下死亡，但一些细胞是雄激素非依赖性的，不需要雄激素来生存。随着时间的推移，存活的细胞开始积极生长。结果是，接受这种疗法的大多数男性会患上复发的肿瘤，并在两年内死亡。为了提高这种治疗的有效性，我们假设，在雄激素治疗前列腺癌后，应用可调控的重组系统来靶向表达白喉毒素(DT-A)到雄激素非依赖性癌细胞将是阻止肿瘤复发的有效方法。我们提出了一种策略，利用复制缺陷型腺病毒载体将DT-A特异性地输送到雄激素非依赖性前列腺癌细胞。这种剧毒蛋白在细胞中的调节表达将导致它们的死亡。我们将在培养的人类前列腺癌细胞、由这些细胞培育出的小鼠的异种移植瘤以及转基因小鼠的前列腺癌模型中测试这种方法的有效性。我们希望我们的研究能为前列腺癌患者开发一种新的基因疗法，有效地阻止复发肿瘤的发展。

DESCRIPTION (provided by applicant): The standard therapy for men with metastatic prostate cancer is to reduce tumor size by androgen ablation, either by bilateral orchiectomy or the use of luteinizing hormone-releasing hormone analogues. While many prostate cancer cells die in the absence of androgens, some cells are androgen-independent and do not require androgens for survival. With time, the surviving cells begin to grow aggressively. The result is that most men receiving this therapy develop recurrent tumors and die within two years. To improve the effectiveness of this therapy, we hypothesize that following androgen ablation therapy for the treatment of prostatic carcinoma, application of a regulated recombination system to target expression of diphtheria toxin (DT-A) to androgen independent cancer cells would be an effective way to arrest the development of recurrent tumors. We propose a strategy to use replicative-defective adenoviral vectors to deliver DT-A specifically to androgen-independent prostate cancer cells. The regulated expression of this highly toxic protein in cells will result in their death. We shall test the effectiveness of this approach in cultured human prostate cancer cells, in xenografts in mice developed from such cells, and in prostate tumors in a transgenic mouse model. We expect our investigations will lead to the development of a novel gene therapy for prostate cancer patients that will effectively arrest the development of recurrent tumors.