AMYLOIDOGENESIS ROLE OF REACTIVE ASTROCYTES

反应性星形胶质细胞的淀粉样生成作用

• 批准号: 6345206
• 负责人: CARMELA R ABRAHAM
• 金额: $ 0.18万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6345206
• 关键词: biomedical resource; cardiovascular system; clinical research; clinical trials; female; hematology; human subject; male; neoplasm /cancer; orphan disease /drug; proteins; technology /technique; transplantation; biomedical resource; cardiovascular system; clinical research; clinical trials; female; hematology; human subject; male; neoplasm /cancer; orphan disease /drug; proteins; technology /technique; transplantation

Arnyloidosis of the AL type, due to depositions of clonal immunoglobulin (1g) light chains, is a rare plasma cell neoplasm (2,500 new cases annually in the USA) and a rapidly progressive orphan disease with a poor prognosis. Death usually occurs 2 to 3 years after diagnosis due to organ failure despite oral therapy with melphalan and prednisone. Since July 1994, in our multidisciplinary Amyloid Program that is dedicated to finding an effective therapy forthis disease, we have treated patients in Phase I and 11 trials with intravenous (IV) melphalan (FDA END #41,776) and mobilized blood stem-cell support. Results indicate feasibility and efficacy; indeed, the therapy is so much more effective than any current treatment that it is ethically difficult to design a clinical trial to evaluate it. We are testing, therefore, in a stratified randomized prospective Phase II clinical trial, the hypothesis that treating patients within I year of diagnosis with IV melphalan and blood stem-cell support is as effective as treating patients with 2 cycles of oral therapy followed by IV melphalan. Patients are followed at 3-month intervals to assess progressive amyloidosis, plasma cell response to therapy and quality of life. In order to test thehypotheses that clonal malignant cell contamination in stem-cell collections increases with mobilization and correlates inversely with duration of response to therapy, all patients have serial marrow and blood specimens, pre- and post-mobilization blood specimens and stem-cell collections, evaluated by PCR for rearranged Ig heavy chain genes. After cloning and sequencing, responding patients amplified genetic material, tumor-specific primers are constructed in order to quantitate with competitive PCR the tumor burden in patient samples. The significance of this work lies in defining an effective therapy for this rare and rapidly fatal disease. MALDI and ESI mass spectrometry are being utilized to characterize the Ig light chain material excreted in patient urine, in order to assist in definition of the biochemical consequences of the disease and treatment.

由于克隆的沉积，Al类型的砷病 免疫球蛋白（1G）轻链是罕见的浆细胞肿瘤 （美国每年有2,500例新案件）和一个快速进步的孤儿 预后不良的疾病。 死亡通常发生2至3年 诊断后由于口腔疗法而导致器官衰竭的诊断 Melphalan和泼尼松。 自1994年7月以来，在我们的多学科 致力于寻找有效疗法的淀粉样蛋白计划 Forthis病，我们在第一阶段和11次试验中治疗了患者 静脉内（IV）Melphalan（FDA末端＃41,776）和动员血液 干细胞支撑。 结果表明可行性和功效；的确， 该疗法比目前的任何治疗都要有效得多，以至于 在道德上很难设计临床试验来评估它。 因此，我们正在测试分层的前瞻性 II期临床试验，这是对治疗患者在内的假设 i的静脉内诊断和血干细胞支持的一年是 与治疗2个口服治疗的患者一样有效 其次是IV Melphalan。 以3个月的间隔遵循患者 为了评估进行性淀粉样变性，血浆细胞对治疗的反应和 生活质量。 为了测试克隆恶性肿瘤 干细胞收集中的细胞污染随着 动员并与响应持续时间相反 治疗，所有患者均具有连环骨髓和血液标本，前和 润滑后血样和干细胞收集，评估 通过PCR进行重新排列的IG重链基因。 克隆后 测序，反应的患者放大遗传物质， 构建肿瘤特异性引物是为了定量 竞争性PCR患者样品中的肿瘤负担。 意义 这项工作在于为这种罕见的和 快速致命的疾病。 MALDI和ESI质谱正在 用来表征排出的IG轻链材料 患者尿液，以帮助定义生化 疾病和治疗的后果。