EFFECTS OF NONUNIFORM DISTRIBUTIONS OF RADIOACTIVITY

有许多因素决定了生物反应 含有放射性的组织，如放射敏感性，分布 放射性、放射性核素发出的辐射的类型和数量， 放射性核素的生物学特性、修复时间等。传统上， 计算对组织的吸收剂量 平均吸收剂量。然而，组织中的不均匀活性分布 在多细胞和亚细胞水平导致不均匀的剂量， 因此，很难充分关联生物反应， 平均吸收剂量。这是诊断和治疗中的一个重要问题。 治疗性核医学在诊断的情况下， 原则上，辐射损伤可以被大大低估， 导致诱发癌症风险增加。相反，患者可能会过度- 或在癌症的放射性核素治疗中治疗不足。过度治疗或 放射性核素治疗癌症的治疗不足可能会产生非常不利的 对患者的最终结果有影响。虽然计算 细胞水平的吸收剂量一直被提倡作为解决 这个问题，这个在很大程度上还是一个理论上的问题。申请人 假设含有掺入的组织的生物学反应 放射性核素可与吸收剂量相关， 细胞水平。为了验证这一假设，一种新的体外多细胞簇 将使用一个能够严格控制变量的模型。多细胞 将用含有放射性的哺乳动物细胞组装成簇， 将确定作为簇活性的函数的细胞存活分数 对于几种不同的放射性药物， 粒子或俄歇电子。不同百分比的细胞将被 用不同的放射性化学物质标记，以确定不均匀的 放射性在细胞和亚细胞水平的分布。通过 通过控制标记细胞的百分比，该模型还将用于 确定旁观者效应在生物效应中的作用 结合放射性。这些数据和细胞剂量计算将 用于开发理论模型，以预测基于细胞的反应， 吸收剂量和旁观者效应。这项研究的结果是预期的 对理解和预测生物反应有重大影响 肿瘤和正常组织的放射性分布不均匀。

There are numerous factors that determine the biological response of tissues that contain radioactivity such as radiosensitivity, distribution of radioactivity, type and number of radiations emitted by the radionuclide, biokinetics of the radionuclide, repair time, etc. Traditionally, the mean absorbed dose to the tissue is calculated to correlate the biological response with mean absorbed dose. However, nonuniform activity distributions in tissue at the multicellular and subcellular levels result in nonuniform doses and therefore have made it difficult to adequately correlate biological response with mean absorbed dose. This is an important problem in diagnostic and therapeutic nuclear medicine. In the case of diagnosis, the risk of the radiation insult can in principle be drastically underestimated and potentially lead to increased risk of inducing cancer. In contrast, patients can be over- or under-treated in radionuclide therapy of cancer. Over-treatment or under-treatment in radionuclide therapy of cancer can have very adverse consequences in the final outcome for the patient. While calculation of absorbed dose at the cellular level has been advocated as a means to address this problem, this has largely remained a theoretical exercise. The applicants hypothesize that the biological response of tissues containing incorporated radionuclides can be correlated with absorbed dose when calculated at the cellular level. To test the hypothesis, a novel in vitro multicellular cluster model will be used which allows tight control over variables. Multicellular clusters will be assembled with mammalian cells containing radioactivity and the cell survival fraction as a function of cluster activity will be determined for several different radiopharmaceuticals which emit alpha particles, beta particles, or Auger electrons. Different percentages of the cells will be labeled with the different radiochemicals to ascertain the impact of nonuniform distributions of radioactivity at the cellular and subcellular levels. By controlling the percentage of cells labeled, this model will also be used to ascertain the role of bystander effects in the biological effects of incorporated radioactivity. These data and cellular dosimetry calculations will be used to develop a theoretical model to predict response based on cellular absorbed dose and bystander effects. The outcome of this research is expected to have a major impact on understanding and predicting the biological response of tumor and normal tissue to nonuniform distributions of radioactivity.