MURINE LYMPHOCYTE SCE MODEL FOR PREDICTING GENOTOXIC RIS

外周血淋巴细胞姐妹染色单体交换（SCE）分析 （PBL）通常用作人类遗传毒性暴露的指标 人口。 本提案的主要目的是检验假设： 未修复SCE诱导病变的积累及其持续性 在PBL中，由反复的化学暴露产生，与 药剂的致瘤活性 由于人体研究的固有局限性， 在人类PBL中持续升高的SCE和在关键的 身体组织和/或致癌作用最多是推断出来的。 所以作为 为了检验我们的假设，我们描述了一种平行四边形方法，该方法： 1.比较鼠和人PBL SCE对已知致癌物的反应， L-苯丙氨酸氮芥（L-PAM），和 2.比较小鼠PBL SCE反应与其他关键组织中的反应 在用各种致癌化学物质处理小鼠后， 活动 对于本研究的第一部分，一个非常大的L-PAM治疗的患者SCE 数据库可从当地的一项研究中获得。 这使我们能够设计 等效的鼠L-PAM治疗方案，以确定是否 SCE反应中观察到相同的一般治疗后趋势， 人和鼠PBL。 在研究的第二部分，L-PAM和，如果时间允许，其他 使用建立的肺将烷化剂给予小鼠 腺瘤测定方案。 将在PBL、脾、淋巴中评价SCE 淋巴结和胸腺淋巴细胞在不同时间间隔（24小时- 15周） 最后一次治疗后。 将讨论以下问题： 对所提出的动物模型的成功评价将为 为将来的研究。 例如，一种化学物质， 在高剂量和低剂量下， 动物模型，以确定人类遗传毒性风险。 此外，本发明还提供了一种方法， 可以在动物模型中评估新的化学物质， 在人类广泛接触之前就存在遗传毒性风险。

Analysis of sister chromatid exchange (SCE) in peripheral blood lymphocytes (PBLs) is commonly used as an indicator of genotoxic exposures of human populations. The primary goal of this proposal is to test the hypothesis: The accumulation of unrepaired SCE-inducing lesions and their persistence in PBLs, produced by repeated chemical exposure, are directly related to the agent's tumorigenic activity. Due to inherent limitations of human studies any association of acute or persistently elevated SCEs in human PBL and genotoxic damage in critical body tissues and/or carcinogenesis is, at best, inferred. Therefore, as a means of testing our hypothesis we describe a parellelogram approach which: 1. Compares murine and human PBL SCE responses to a known carcinogen, L-phenylalanine mustard (L-PAM), and 2. Compares murine PBL SCE responses to responses in other critical tissues following treatment of mice with chemicals of varying carcinogenic activities. For the first part of this study a very large L-PAM-treated patient SCE data base is available from a local study. This enables us to design equivalent murine L-PAM treatment protocols in order to determine whether the same general post-treatment trends in SCE responses are observed in human and murine PBLs. In the second part of the study, L-PAM and, if time permits, other alkylating agents will be administered to mice using the established lung adenoma assay protocol. SCEs will be evaluated in PBLs, spleen, lymph node, and thymus lymphocytes at various time intervals (24 hrs - 15 wks) after the last treatment. The following questions will be addressed: Successful evaluation of the proposed animal model will provide the basis for future studies. For example, a chemical which produces ambiguous SCE results in humans can be more completely evaluated at high and low doses in the animal model in order to determine human genotoxic risk. In addition, new chemicals can be evaluated in the animal model in order to predict genotoxic risk prior to wide spread human exposure.