Vitamin D in Prostate Cancer: Tumor Vasculature Effects

描述(由申请人提供)：我们已经证明了最活跃的 维生素D部分1，25二羟基胆钙醇(骨化三醇)具有显著的 体内和体外的抗增殖活性。骨化三醇诱导G0/G1期 阻断，调节p27/p21，诱导细胞凋亡，增强抗肿瘤作用 顺铂、卡铂、紫杉醇和多西紫杉醇的活性。在体外和在 体内地塞米松(Dex)增强骨化三醇介导的抗肿瘤活性 与维生素D受体(VDR)的配体结合并增强 VDR蛋白表达。骨化三醇/地塞米松也抑制激活 丝裂原活化蛋白激酶(MAPK，ERT 1/2)活性和磷酸化 AKT(P-Akt)。激素难治性前列腺癌的II期临床试验 使用大剂量口服骨化三醇和地塞米松，我们观察到 28%的NO患者血清前列腺特异性抗原(PSA)检测 高钙血症；VDR和其他潜在的骨化三醇标志物的调节 外周血单核细胞的活性。我们有初步数据显示 骨化三醇和地塞米松诱导细胞凋亡，调节细胞周期，减少 P-Erk 1/2和P-Ark及VDR表达显著上调 肿瘤来源的内皮细胞(TDEC)与内皮细胞的比较 分离自正常组织(主动脉)。这些研究表明， 骨化三醇/地塞米松抗肿瘤作用机制(S) 肿瘤内血管构筑。我们建议通过以下几点来检验这一假设 具体目标：1)确定骨化三醇/地塞米松的作用机制 前列腺癌组织中分离的TDEC与正常对照的作用 检测：a)对细胞凋亡和细胞周期的影响；b)对侵袭性的影响， 运动性和血管生成；以及c)活动是否需要骨化三醇 结合VDR；2)确定TDEC在前列腺癌模型中的作用 在骨化三醇/地塞米松的抗肿瘤作用中，通过确定：a)对 肿瘤内的血管形成；b)治疗动物分离的TDEC的影响 与骨化三醇的关系；以及c)在调节 对TDEC和抗肿瘤作用的影响以及3)评价口服骨化三醇(12 mg QDx3)和/或地塞米松(4 Mg QDx4)给局限型患者每周×4次 前列腺癌在前列腺癌切除前立即确定：a)对 肿瘤内皮细胞；b)细胞周期状态、凋亡标志物和 前列腺上皮内瘤变(PIN)与前列腺特异性抗原 (PSA)响应。

DESCRIPTION (provided by applicant): We have demonstrated that the most active vitamin D moiety 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27/p21, induces apoptosis and enhances the antitumor activity of cisplatin, carboplatin, paclitaxel and docetaxel. In vitro and in vivo, dexamethasone (dex) potentiates calcitriol-mediated antitumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo and enhances VDR protein expression. Calcitriol/dex also suppress activated mitogen-activated protein kinase (MAPK), Ert 1/2) activity and phosphorylated Akt (P-Akt). In a phase II clinical trial of hormone refractory prostate cancer with high dose oral calcitriol and dex, we observed a 50 percent reduction in serum prostate specific antigen (PSA) in 28 percent of patients with no hypercalcemia; modulation of VDR and other potential markers of calcitriol activity in peripheral blood monocytes. We have preliminary data indicating that calcitriol and dex induces apoptosis, modulates cell cycle, decreases P-Erk 1/2 and P-Ark and significantly up-regulated VDR expression of tumor-derived endothelial cells (TDEC) as compared to endothelial cells isolated from normal tissues (aortic). These studies suggest that the mechanism(s) of calcitriol/dex antitumor activity may involve effects on intratumor vasculature. We propose to examine this hypothesis by the following Specific Aims: 1) to determine the mechanisms involved in calcitriol/dex effects in TDEC isolated from prostate tumors as compared to normal by examining: a) effects on apoptosis and cell cycle; b) effects on invasiveness, motility, and angiogenesis; and c) whether activities require calcitriol binding to the VDR; 2) To determine the prostate tumor models the role of TDEC in calcitriol/dex antitumor effects by determining: a) effects on the vasculature within the tumor; b) effects on TDEC isolated from animals treated with calcitriol; and c) whether a relationship exists between modulation of effects on TDEC and antitumor effects and 3) To evaluate oral calcitriol (12mg QDx3) and/or dex (4mg QDx4) administered weekly x 4 to patients with localized prostate cancer immediately prior to prostatectomy to determine: a) effects on tumor endothelial cells; b) effects of cell cycle status, apoptosis markers and prostatic intraepithelial neoplasia (PIN) and c) prostate specific antigen (PSA) response.