S179D Prolactin: Inhibition of Prostate Cancer Growth

S179D 催乳素：抑制前列腺癌生长

• 批准号: 6790880
• 负责人: AMEAE M WALKER
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790880
• 关键词: apoptosis; athymic mouse; cell line; chorionic gonadotropin; dosage; drug resistance; drug screening /evaluation; growth inhibitors; hormone receptor; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; immunologic assay /test; immunoprecipitation; microarray technology; neoplasm /cancer therapy; neoplastic growth; nonhuman therapy evaluation; northern blottings; polymerase chain reaction; prolactin; prolactin releasing /inhibiting factor; prostate neoplasms; receptor expression; urinalysis; western blottings

DESCRIPTION (Provided by the applicant) Prostate cancer is the second leading cause of cancer deaths among males in the United States. While effective treatments exist for as long as the tumors remain sensitive to androgens, there are no good therapies available once evolution to an androgen-insensitive state occurs. An evaluation of factors which contribute to the growth of these later stage tumors is crucial to the development of new therapeutic strategies. Prolactin (PRL) is one such factor. Although large quantities of PRL are produced by the pituitary, PRL also serves as an autocrine growth factor in the normal human prostate and, as we have shown, this autocrine growth loop continues to be operative in cells representative of highly metastatic, androgen-independent cancers. Using a novel PRL growth antagonist developed in our laboratory, S179D PRL, we have demonstrated that blockade of the PRL autocrine growth loop reduces both the growth of well-established tumors and tumor initiation when androgen-independent cancer cells are grown in nude mice. This PRL growth antagonist therefore has the potential to be an important new therapeutic for late stage disease. The overall aim of the proposed project is to gain a fuller understanding of the molecular and cellular mechanisms underlying S179D PRL's antagonism of prostate tumor growth so that the full potential of this therapeutic can be realized. The specific aims are 1) to determine the optimal dose of S179D PRL, 2) to establish whether S179D PRL slows or halts growth or actually reduces tumor size, 3) to determine whether resistance can develop, and 4) to determine whether any aspect of the growth inhibition involves a) the promotion of apoptosis, or b) downregulation of the growth-promoting PRL autocrine loop, or c) upregulation of the short PRL receptor. In most experiments tumor size will be monitored by the amount of a secreted transfected gene product in the urine. In this way, individual nude mice can be assessed for their response to treatment. S179D PRL will be administered by Alzet minipumps implanted subcutaneously. Molecular and cellular effects on the tumors/tumor cells will be assessed by end-labeling for apoptosis, Northern, Western and microarray analysis for gene expression and immunoprecipitation, Western and radiolabel incorporation for signaling.

描述（由申请人提供） 前列腺癌是美国男性癌症死亡的第二大原因。 美国的虽然有效的治疗方法只要肿瘤存在 仍然对雄激素敏感，没有好的治疗方法，一旦 发生向雄激素不敏感状态的进化。因素评价 这有助于这些晚期肿瘤的生长， 开发新的治疗策略。催乳素（PRL）就是其中之一。 虽然垂体分泌大量的催乳素，但催乳素也 作为正常人前列腺的自分泌生长因子， 如图所示，这种自分泌生长循环在细胞中继续起作用 代表高度转移的雄激素非依赖性癌症。使用 本实验室研制的一种新型PRL生长拮抗剂S179 D PRL， 表明阻断PRL自分泌生长环既降低了 已建立的肿瘤的生长和肿瘤起始， 雄激素非依赖性癌细胞在裸鼠中生长。这种PRL的增长 因此，拮抗剂有可能成为一种重要的新的治疗药物， 晚期疾病拟议项目的总体目标是获得更全面的 了解S179 D PRL的分子和细胞机制 前列腺肿瘤生长的拮抗作用， 可以实现治疗。具体目标是：（1）确定最佳 S179 D PRL剂量，2）确定S179 D PRL是否减缓或停止生长，或 实际上减少了肿瘤的大小，3）确定是否会产生耐药性， 和4）确定生长抑制的任何方面是否涉及a） 促进细胞凋亡，或B）下调促生长PRL 自分泌环，或c）短PRL受体的上调。在大多数 实验中肿瘤大小将通过分泌的 在尿液中发现了转染的基因产物。通过这种方式，可以将单个裸鼠 评估他们对治疗的反应。S179 D PRL将由以下人员给药 皮下植入Alzet微型泵。分子和细胞对 肿瘤/肿瘤细胞将通过末端标记凋亡，北方， Western和微阵列分析基因表达和免疫沉淀， Western和放射性标记掺入用于信号传导。