Calcitriol for Chemoprevention in Preinvasive Bronchial Epithelial Lesions

骨化三醇用于侵袭前支气管上皮病变的化学预防

• 批准号: 6985075
• 负责人: GREGORY M LOEWEN
• 金额: $ 65.22万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-21 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985075
• 关键词: 1,25 dihydroxycholecalciferol; BCL2 gene /protein; apoptosis; biomarker; bronchoscopy; bronchus neoplasm; cancer prevention; cell proliferation; chemoprevention; clinical research; clinical trial phase II; diet therapy; dietary supplements; drug screening /evaluation; growth factor receptors; histopathology; human subject; human therapy evaluation; immunocytochemistry; neoplastic growth; preneoplastic state; respiratory epithelium; smoking; smoking cessation

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States, and it is estimated that 171,900 new cases will be diagnosed in 2003. It is estimated that 157,200 of these patients will ultimately die from their lung cancer, primarily because they will have advanced stage disease at the time of diagnosis. The burden of lung cancer is not shouldered exclusively by people who continue to smoke cigarettes. While 40-50 million Americans have stopped smoking, their risk of developing lung cancer remains high for as many as 30 years after smoking cessation. Vitamin D [1,25 dihydroxycholecalciferol (calcitriol)] is a potent anti-proliferative agent in a variety of malignant cell types, including human squamous cell carcinoma (SCC) and human xenograft lung cancer. The chemopreventive activity of calcitriol in modulating expression of markers of tissue damage, including proliferation (MCM2), disruption of apoptotic pathways (Bcl-2), the epidermal growth factor receptor (EGFR), AKT and will be evaluated. For this study, high-risk former smokers with premalignant lesions (squamous metaplasia or dysplasia) documented by autofluorescence (AF) bronchoscopy will be recruited as subjects in the Phase II study. We propose to examine the potential chemoprevention effect of calcitriol for inhibiting the progression of dysplasia and metaplasia, and for the prevention of new premalignant lesions detectable with AF bronchoscopy, and for altering biomarkers expression, using a 6-month incomplete crossover design that will randomize subjects to either a placebo or 16 meg of calcitriol for 3 days per week. Serial AF bronchoscopies at 6 and 12 months after randomization will demonstrate the efficacy of this potential chemopreventive agent for progression premalignant bronchial epithelial lesions. The Primary Hypothesis for this study is that calcitriol will prevent the progression of metaplastic or dysplastic lesions at specific sites in the bronchial epithelium and will inhibit the formation of new dysplastic or metaplastic lesions throughout the lung field. The secondary hypotheses is that calcitriol will alter biomarkers of apoptosis and growth signaling in the bronchial epithelium, and that calcitriol supplementation three days per week will show an acceptable toxicity profile.

描述（申请人提供）： 肺癌是美国癌症死亡的主要原因，估计 2003 年将诊断出 171,900 例新病例。估计其中 157,200 名患者最终将死于肺癌，主要是因为他们在诊断时已处于晚期疾病。肺癌的负担不仅仅由继续吸烟的人承担。虽然 40-5000 万美国人已经戒烟，但在戒烟后长达 30 年内，他们患肺癌的风险仍然很高。维生素 D [1,25 二羟基胆钙化醇（骨化三醇）] 是多种恶性细胞类型的有效抗增殖剂，包括人鳞状细胞癌 (SCC) 和人异种移植肺癌。将评估骨化三醇在调节组织损伤标志物表达方面的化学预防活性，包括增殖 (MCM2)、细胞凋亡途径破坏 (Bcl-2)、表皮生长因子受体 (EGFR)、AKT。在这项研究中，通过自发荧光 (AF) 支气管镜检查记录的具有癌前病变（鳞状化生或发育不良）的高危前吸烟者将被招募为 II 期研究的受试者。我们建议检查骨化三醇的潜在化学预防作用，以抑制不典型增生和化生的进展，预防通过 AF 支气管镜检查可检测到的新癌前病变，以及改变生物标志物的表达，使用将受试者随机化的 6 个月不完全交叉设计每周 3 天服用安慰剂或 16 兆克骨化三醇。随机化后 6 个月和 12 个月的连续 AF 支气管镜检查将证明这种潜在化学预防剂对进展性支气管上皮病变进展的功效。本研究的主要假设是骨化三醇将阻止支气管上皮特定部位化生或发育不良病变的进展，并抑制整个肺野新的发育不良或化生病变的形成。第二个假设是骨化三醇会改变支气管上皮细胞凋亡和生长信号的生物标志物，并且每周补充三天骨化三醇将显示出可接受的毒性特征。