Targeted Death of Prostatic Cancer Cells

前列腺癌细胞的靶向死亡

• 批准号: 6574134
• 负责人: JANET A SAWICKI
• 金额: $ 33.38万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574134
• 关键词: Adenoviridae; androgen inhibitor; biotechnology; cell death; cell growth regulation; cell line; combination cancer therapy; diphtheria toxin; gene delivery system; gene targeting; gene therapy; green fluorescent proteins; laboratory mouse; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; neoplastic cell; nonhuman therapy evaluation; polymerase chain reaction; prostate neoplasms; terminal nick end labeling; transfection /expression vector

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.

描述（由申请人提供）：转移性前列腺癌男性患者的标准治疗是通过雄激素消融（双侧睾丸切除术或使用促黄体生成素释放激素类似物）来减小肿瘤大小。 虽然许多前列腺癌细胞在缺乏雄激素的情况下死亡，但一些细胞是雄激素非依赖性的，并且不需要雄激素来存活。 随着时间的推移，存活的细胞开始积极生长。 结果是，大多数接受这种治疗的男性会出现复发性肿瘤，并在两年内死亡。 为了提高这种治疗的有效性，我们假设，在雄激素消融治疗前列腺癌后，应用调节重组系统靶向表达白喉毒素（DT-A）的雄激素非依赖性癌细胞将是一种有效的方法来阻止复发性肿瘤的发展。 我们提出了一种策略，使用复制缺陷型腺病毒载体提供DT-A特异性雄激素非依赖性前列腺癌细胞。 这种高毒性蛋白在细胞中的调节表达将导致细胞死亡。 我们将测试这种方法在培养的人前列腺癌细胞中的有效性，在从这些细胞发育的小鼠异种移植物中，以及在转基因小鼠模型中的前列腺肿瘤中。 我们希望我们的研究将导致一种新的基因治疗前列腺癌患者的发展，将有效地阻止复发性肿瘤的发展。