GLYCOPHORIN A BIODOSIMETRY IN I-131 TREATED PATIENTS

I-131 治疗患者的血型糖蛋白 A 生物剂量测定

• 批准号: 2039490
• 负责人: William L Bigbee
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2039490
• 关键词: bioassay; bone marrow; cell sorting; cryopreservation; gene mutation; glycophorin; hematopoietic stem cells; human subject; iodine; longitudinal human study; lymphocyte; monoclonal antibody; radiation dosage; radiobiology; thyroid disorder; whole body irradiation dosage

The glycophorin A (GPA)-based human in vivo somatic cell mutation assay, because of its demonstrated long-term biological memory of past genotoxic exposures together with its relatively low cost and high sample thruput, is unique among presently available human biomarker assays for practical use as a retrospective biodosimeter in epidemiological investigations of large human populations. Here we propose to further validate the response of the assay as a biodosimeter of radiation exposure in a longitudinal study of patients receiving 131I therapy for thyroid disease. These patients will receive clinically well-characterized doses ranging from 2 to 200 cGy of whole body bone marrow exposure to ionizing radiation resulting from the radioactive decay of administered 131I. Peripheral blood samples from approximately 100 patients will be drawn prior to, during, and following therapy to follow the induction, accumulation, and persistence of radiation-induced somatic mutation at the GPA locus in bone marrow stem cells. These mutations in nucleated bone marrow progenitor cells give rise to erythrocytes in the peripheral circulation expressing a GPA allele-loss variant phenotype. These variants are directly enumerated in the assay using immunolabeling with GPA allele-specific monoclonal antibodies and flow cytometry. Based on GPA assay results obtained in high radiation dose populations, this study is designed to investigate the radiation-dose- response of the assay over a range of doses that surround the extrapolated doubling dose over background response of the assay of approximately 30 cGy. The longitudinal design of the study, applied to patients receiving relatively low doses of 131I, will permit a test of the practical ultimate sensitivity of the assay by comparing GPA variant cell frequencies in post- therapy samples to those observed in pre-therapy samples within individual patients. This design, where a repeated measures analysis can be applied to individual responses, avoids the limitations inherent in studies using exposed versus matched control populations where inter-individual variability in response and in background frequencies limit the power of the assay to detect small increases in variant cell frequencies induced by low-dose exposures. These data will provide critical information to assess the power of the assay to demonstrate, or to estimate the upper limits of radiation exposures in population surveys of occupationally-exposed workers. In addition, since a number of patients receiving very similar 131I doses will enrolled in the study, the design will also permit an investigation of the range of individual responses in the assay to similar exposures. These data will also contribute significantly to population risk assessment models that attempt to include this heterogeneity as well as narrowing the range of uncertainty surrounding individual estimates of received radiation dose inferred from individual responses in the assay.

血糖素A(GPA)为基础的活体人体细胞突变试验， 因为它证明了对过去遗传毒性的长期生物记忆 曝光及其相对较低的成本和较高的样品产量，是 在目前可用的实际使用的人体生物标志物分析中独一无二 作为大型人群流行病学调查中的一种回溯性生物剂量计 人类人口。在这里，我们建议进一步验证 在一项纵向研究中作为辐射暴露生物剂量计的化验 接受131I治疗的甲状腺疾病患者。这些病人会 接受临床特征良好的剂量范围从2到200 cGy. 全身骨髓暴露于电离辐射，由 ~(131)I的放射性衰变外周血液样本来自 大约100名患者将在之前、期间和之后进行抽样调查 治疗遵循诱导、积累和坚持的原则 辐射诱发骨髓干细胞GPA基因座的体细胞突变 细胞。有核骨髓祖细胞中的这些突变导致 到外周循环中表达GPA等位基因缺失的红细胞 变异的表型。这些变异体在化验中被直接列举 使用GPA等位基因特异性单抗免疫标记和 流式细胞术。基于在高辐射剂量下获得的GPA检测结果 人口，这项研究旨在调查辐射剂量- 检测在外推剂量范围内的响应 测定的本底剂量加倍，约为30% 谢伊。这项研究的纵向设计，应用于患者接受 相对较低的131I剂量，将允许测试实际的终极 比较GPA变异细胞频率对检测的敏感性 治疗样本与个体内治疗前样本中观察到的样本 病人。这种设计，其中可以应用重复测量分析 对于个体响应，避免了研究中使用 暴露人群与匹配的对照人群在个体间 响应和背景频率的可变性限制了 检测由病毒引起的变异细胞频率轻微增加的方法 低剂量暴露。这些数据将为评估提供关键信息 证明，或估计上限的化验能力 职业性接触人群调查中的辐射暴露 工人们。此外，由于一些患者接受的治疗非常相似 131I剂量将参加这项研究，该设计还将允许 对类似物质的个体反应范围的调查 曝光。这些数据也将对人口做出重大贡献 尝试包含这种异质性的风险评估模型 由于缩小了围绕个人估计的不确定范围 从分析中的个体反应推断出的接收辐射剂量。