MUTAGEN SENSITIVITY AND CANCER SUSCEPTIBILITY

诱变剂敏感性和癌症易感性

• 批准号: 3812625
• 负责人: RALPH WEICHSELBAUM
• 金额: --
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3812625
• 关键词: 6 thioguanine; DNA replication; Epstein Barr virus; acute leukemia; alkylating agents; alkylation; alkyltransferase; antileukemic agent; carmustine; cellular oncology; chromosome deletion; chromosome disorders; cytogenetics; drug adverse effect; drug carcinogenesis; drug resistance; gene mutation; genetic transcription; guanine analog; molecular oncology; mutagen testing; mutagens; neoplasm /cancer genetics; neoplastic cell culture for noncancer research; nitrosoguanidines; transposon /insertion element; viral carcinogenesis

Secondary acute nonlymphocytic leukemia (ANLL) is a late complication that occurs in individuals exposed to cytotoxic agents for the treatment of a primary malignant or nonmalignant disease. While exposure to the cytotoxic agents is believed to cause the malignancy, we do not know why the second malignancy develops only in certain individuals, nor why it is this particular malignancy that develops. We propose to continue our studies on the role of mutagen sensitivity in the etiology of secondary ANLL. Peripheral blood lymphocytes (PBLs) obtained from patients with ANLL have been shown to have lower levels of the DNA repair protein O6-alkylguanine alkyltransferase (AGT) than do healthy controls or patients with de novo forms of ANLL. In this project, we will examine the biological importance of these reduced levels of AGT in detail, studying the cellular, cytogenetic and molecular effects of exposure to mono-and bifunctional alkylating agents in six isogenic human lymphoblastoid cell lines with AGT activities ranging from 0-25 fmol/ug DNA cells. The following questions will be addressed; 1) Are lower levels of AGT always associated with increased sensitivity to alkylation-induced mutagenicity? 2) Do different levels of AGT affect the induction of DNA and chromosome breaks by alkylating agents? 3) What are the spectra of mutations induced by alkylating agents in cells with different levels of AGT activity? Understanding the biological significance of reduced AGT activities should provide clues to the etiology of secondary ANLL.

继发性急性非淋巴细胞白血病（ANLL）是一个晚期并发症， 发生在暴露于细胞毒性剂的个体中以治疗 原发性恶性肿瘤或非恶性疾病。而暴露于细胞毒性 据信代理会导致恶性肿瘤，我们不知道为什么第二个 恶性仅在某些人中发展，也不是为什么 发展的特殊恶性肿瘤。我们建议继续学习 诱变素敏感性在次级ANLL病因中的作用。 从ANLL患者获得的外周血淋巴细胞（PBL） 被证明具有较低水平的DNA修复蛋白O6-烷基鸟嘌呤 烷基转移酶（AGT）比健康对照组或从头开始的患者 Anll的形式。在这个项目中，我们将研究生物学的重要性 在这些详细降低的AGT水平中，研究了细胞， 暴露于单功能的细胞遗传学和分子作用 与AGT的六种同源人淋巴母细胞系中的烷基化剂 0-25 FMOL/UG DNA细胞的活性。以下问题 将被解决； 1）始终与AGT相关的较低水平 对烷基化引起的诱变性的敏感性提高？ 2）做不同的 AGT水平会影响DNA和染色体断裂的诱导 烷基化剂？ 3）突变的光谱是由什么引起的 AGT活性水平不同的细胞中的烷基化剂？ 了解减少AGT活动的生物学意义应 为次级ANLL的病因提供线索。