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: 7272843
• 负责人: Mary E Reid
• 金额: $ 23.7万
• 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/7272843
• 关键词: Adverse effects; American; Apoptosis; Apoptotic; Biological Markers; Biopsy; Bronchoscopy; Calcitriol; Cancer Etiology; Carcinoma in Situ; Cell Cycle Regulation; Cell Cycle Regulation Pathway; Cessation of life; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Count; Crossover Design; Development; Diagnosis; Dihydroxycholecalciferols; Disease; Disease regression; Disruption; Dysplasia; End Point; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Evaluation; Exposure to; Growth; Histology; Human; Immunohistochemistry; In Vitro; Invasive; Lesion; Light; Lung; MCM2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Metaplasia; Metaplastic; Modeling; Mucous Membrane; Mutation; Numbers; Oral; Pathway interactions; Patients; Phase II Clinical Trials; Placebos; Population; Premalignant; Prevention; Principal Investigator; Process; Proto-Oncogene Proteins c-akt; Randomized; Recruitment Activity; Risk; Safety; Sampling; Shoulder; Signal Transduction; Site; Smoker; Squamous Metaplasia; Squamous cell carcinoma; Staging; Supplementation; Time; Tissues; Tobacco-Associated Carcinogen; Toxic effect; United States; Visit; Vitamin D; Week; Xenograft procedure; angiogenesis; bronchial epithelium; cancer cell; carcinogenesis; cell type; cigarette smoking; day; follow-up; human MCM2 protein; in vivo; pre-clinical; prevent; programs; response; 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（由申请人提供）：肺癌是美国癌症死亡的主要原因，据估计，将在2003年诊断出171,900例新病例。据估计，这些患者中的157,200例最终将死于肺癌，主要是因为诊断时他们将患有晚期疾病。肺癌的负担并非仅由继续抽烟的人肩负。虽然有4,000万美国人停止吸烟，但在戒烟后30年中，他们患肺癌的风险仍然很高。维生素D [1,25二羟基胆碱钙（钙三醇）]是多种恶性细胞类型的有效抗增殖剂，包括人类鳞状细胞癌（SCC）和人异杂交肺癌。骨化三醇在调节组织损伤标记表达中的化学预防活性，包括增殖（MCM2），凋亡途径的破坏（BCL-2），表皮生长因子受体（EGFR），AKT和AKT和将评估。在这项研究中，在II期研究中，将招募具有自动荧光（AF）支气管镜检查的高风险前吸烟者（鳞状变质或发育不良）。我们建议检验钙三醇对抑制发育不良和化生的进展的潜在化学预防作用，以及预防可通过AF支气管镜检查可检测到的新的预施加性病变，并使用6个月的不完整的交叉设计将其随机驱动器驱逐一次，以供应一个percorter carcitr carcitr calcitr或16 me 16 me 16 me 16 me ccall of af haf骨架的表达，并改变了生物标志物的表达。随机分组后6和12个月的串行AF支气管检查将证明这种潜在的化学预防剂对进展前支气管上皮病变的疗效。这项研究的主要假设是，骨化三醇将防止支气管上皮细胞特定部位的化生或异型损伤的进展，并会抑制整个肺部整个肺场的新不塑性或化生病变的形成。次要假设是，骨化三醇将改变支气管上皮中细胞凋亡和生长信号传导的生物标志物，并且每周三天的钙三醇补充剂将显示出可接受的毒性特征。