S179D Prolactin: Inhibition of Prostate Cancer Growth

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。虽然有效的治疗方法一直存在，但只要肿瘤 仍然对雄激素敏感，一旦有了好的治疗方法 进化到雄激素不敏感状态。影响因素的评价 对这些晚期肿瘤的生长起到关键作用 开发新的治疗策略。催乳素(PRL)就是这样一个因素。 虽然大量的催乳素是由脑下垂体产生的，但催乳素也是 作为正常人类前列腺中的一种自分泌生长因子，我们已经 如图所示，这种自分泌生长环在细胞中继续起作用 高度转移性、雄激素非依赖性癌症的代表。使用 我们实验室开发的新型催乳素生长拮抗剂S179D PRL，我们已经 证明了对PRL自分泌生长环路的封锁既减少了 已建立的肿瘤的生长和肿瘤的发生 雄激素非依赖性癌细胞在裸鼠体内生长。这一PRL增长 因此，拮抗剂有可能成为一种重要的新的治疗方法 晚期疾病。拟议项目的总体目标是获得更全面的 了解S179D PRL的分子和细胞机制 拮抗前列腺癌的生长，使之充分发挥潜能 治疗是可以实现的。其具体目标是：1)确定最优 剂量S179D PRL，2)确定S179D PRL是否减慢或停止生长或 实际上缩小了肿瘤的大小，3)以确定是否会产生耐药性， 以及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)下调促进生长的催乳素 自分泌环，或c)短PRL受体上调。在大多数 实验肿瘤的大小将通过分泌量进行监测 尿液中的转基因产物。通过这种方式，单个裸鼠可以 评估他们对治疗的反应。S179D PRL将由 阿尔茨海默病微泵植入皮下。分子和细胞效应对细胞的影响 肿瘤/肿瘤细胞将通过末端标记的凋亡，Northern， 基因表达和免疫沉淀的Western和微阵列分析， WESTERN和RADIOLABEL信号的并入。

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.