Chemoprevention of Pituitary Corticotroph Tumors

垂体促肾上腺皮质激素肿瘤的化学预防

• 批准号: 6929660
• 负责人: ANTHONY P HEANEY
• 金额: $ 7.8万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-11 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929660
• 关键词: Cushing' s syndrome; adipocytes; adrenocorticotropic hormone; apoptosis; blood glucose; blood tests; chemoprevention; corticosterone; cortisol; cytokine; dietary lipid; genetically modified animals; histopathology; hormone related neoplasm /cancer; imidazole; laboratory mouse; ligands; liver function; nutrition aspect of cancer; obesity; peroxisome proliferator activated receptor; pituitary neoplasms; triterpenes; urinalysis

DESCRIPTION (provided by applicant): Cushing's disease, due to an ACTH-secreting pituitary tumor, causes illness due to excess steroid production; no suitable drug therapies are available, and surgical excision, is not always curative. We have demonstrated that ACTH-secreting pituitary tumors express abundant peroxisome proliferators activated receptor-gamma (PPAR-gamma). PPAR-gamma and the retinoid X receptor (RXR) form a permissive heterodimer, that can be activated by either PPAR-gamma and/ or RXR-specific ligands to regulate target gene transcription. Several natural occurring and synthetic PPAR-gamma ligands, including the thiazolidinedione (TZD), rosiglitazone; the non-TZD, GW7845; and the triterpenoid, cyano-3,12- dioxooleaneana-1,9(11)-dien-28-oyl]imidazole (CDDO-IM) bind PPAR-gamma, to regulate multiple actions. PPAR-gamma activation plays a critical role in adipogenesis, glucose metabolism, and placental function, and TZD's are widely used to treat diabetes. Treatment of human and mouse corticotroph pituitary tumor cells in vitro with PPAR-gamma ligands, inhibited tumor growth, and induced corticotroph tumor apoptosis. When athymic Nu/ Nu mice harboring subcutaneous xenografted corticotroph tumors, were treated with rosiglitazone, 4 of 5 treated mice did not develop tumors. Furthermore, plasma ACTH and corticosterone hormone levels were lower in rosiglitazone-treated animals. In addition, rosiglitazone, given to two patients with Cushing's disease, decreased 24 hour urinary cortisol levels by approximately 55% in one patient, and normalized cortisol levels in the second patient. Recently, we have demonstrated potent anti-proliferative, and pro-apoptotic actions of the PPAR-gamma ligand CDDO-IM in corticotroph tumor cells, using 1000-fold lower concentrations than rosiglitazone. This project will examine the chemopreventative actions of CDDO-IM in vivo in the Rb heterozygote knock-out mouse that develops spontaneous pituitary corticotroph tumor. We will also examine the effects of a high fat diet on pituitary corticotroph tumor development, and examine the role of chemopreventative anti-inflammatory treatment with CDDO-IM in the corticotroph tumor model. Our ultimate goal is to develop a rationale for clinical application of these PPAR-gamma ligands as a novel medical therapy in Cushing's disease.

描述（由申请人提供）：由于分泌垂体的垂体肿瘤，由于类固醇过量而导致疾病，Cushing的疾病会导致疾病；没有合适的药物疗法可用，并且手术切除并不总是治愈的。我们已经证明，分泌垂体肿瘤表达丰富的过氧化物酶体增殖物激活的受体伽马（PPAR-GAMMA）。 PPAR-GAMMA和类维生素X受体（RXR）形成允许的异二聚体，可以通过PPAR-GAMMA和/或RXR特异性配体激活，以调节靶基因转录。几种自然发生的和合成的PPAR-gamma配体，包括噻唑烷二酮（TZD），罗格列酮；非TZD，GW7845;和三萜类化合物3,12-二氧化二氧化碳-1,9（11）-dien-28-28-oyl]咪唑（CDDO-IM）结合PPAR-GAMMA，以调节多种动作。 PPAR-GAMMA激活在脂肪生成，葡萄糖代谢和胎盘功能中起着至关重要的作用，而TZD广泛用于治疗糖尿病。用PPAR-GAMMA配体在体外治疗人和小鼠皮质营养垂体肿瘤细胞，抑制肿瘤的生长，并诱导皮质营养性肿瘤凋亡。当含有皮下异种移植的皮质营养肿瘤的无胸腺nu/ nu小鼠用罗格列酮治疗，5例治疗的小鼠中有4只没有出现肿瘤。此外，在金甲酮治疗的动物中，血浆ACTH和皮质酮激素水平较低。此外，给予两名库欣病患者的罗格列酮可在一名患者中降低24小时尿皮质醇水平约55％，并使第二名患者的皮质醇水平归一化。最近，我们使用比索加列唑酮低1000倍，证明了PPAR-GAMMA配体CDDO-IM在皮质营养肿瘤细胞中PPAR-GAMMA配体CDDO-IM的有效抗增殖和促凋亡作用。该项目将检查CDDO-IM在Rb杂合子敲除小鼠中的化学预防作用，该小鼠会发展出自发性皮质营养性肿瘤。我们还将检查高脂饮食对垂体皮质营养肿瘤发育的影响，并检查CDDO-IM在皮质营养型肿瘤模型中使用CDDO-IM进行化学预防抗炎治疗的作用。我们的最终目标是为这些PPAR-GAMMA配体作为库欣氏病的新药物疗法而促进临床应用的基本原理。