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) 是一种晚期并发症， 发生在接触细胞毒性药物以治疗某种疾病的个体中 原发性恶性或非恶性疾病。当暴露于细胞毒性物质时 据信制剂会导致恶性肿瘤，我们不知道为什么第二个 恶性肿瘤仅在某些个体中发生，也不知道为什么会这样 发生的特定恶性肿瘤。我们建议继续研究 诱变剂敏感性在继发性 ANLL 病因学中的作用。 从 ANLL 患者获得的外周血淋巴细胞 (PBL) 已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) 高于健康对照或新发患者 ANLL 的形式。在这个项目中，我们将研究生物学的重要性 详细研究这些 AGT 水平降低的细胞， 暴露于单功能和双功能的细胞遗传学和分子效应 六种具有 AGT 的同基因人淋巴母细胞系中的烷化剂 活性范围为 0-25 fmol/ug DNA 细胞。以下问题 将得到解决； 1) 较低水平的 AGT 是否总是与 对烷基化诱导的致突变性的敏感性增加？ 2）做不同的事 AGT 水平影响 DNA 和染色体断裂的诱导 烷化剂？ 3) 引起的突变谱是怎样的 具有不同 AGT 活性水平的细胞中的烷化剂？ 了解 AGT 活性降低的生物学意义应该 为继发性 ANLL 的病因学提供线索。