PROTECTION OF LUNG FROM CYTOTOXIC DRUGS

保护肺部免受细胞毒性药物的侵害

• 批准号: 6563890
• 负责人: William J Martin
• 金额: $ 22.01万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563890
• 关键词: DNA damage; DNA repair; adduct; antineoplastics; bleomycin; combination cancer therapy; cytotoxicity; disease /disorder model; drug resistance; drug screening /evaluation; endonuclease; genetic manipulation; genetically modified animals; human tissue; intracellular; laboratory mouse; lung injury; methyltransferase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; nitrosourea; pharmacokinetics; pulmonary fibrosis /granuloma; respiratory epithelium; transfection /expression vector

Cancer chemotherapeutic agents such as bleomycin and the chloroethylnitrosureas (CENU) are associated with a high incidence of pulmonary toxicity. The lung injury and fibrosis induced by these drugs represents a major limiting factor in the therapeutic efficacy of these drugs in the treatment of cancer. Both bleomycin and CENU cause DNA damage by mechanisms including creation of apurinic/apyrimidinic (AP) sites, strand scissions and abnormal DNA adducts which lead to cell death. Pulmonary toxicity from cytotoxic drugs is typically associated with injury to the pulmonary capillary endothelium and the type I and type II alveolar epithelial cells. This project will focus on the role of specific DNA repair proteins in protecting lung cells from the DNA damaged caused by bleomycin or CENU and by hyperoxia, a condition associated with exacerbation of drug-induced lung disease. It is proposed that specific DNA repair proteins such as apurinic/apyrimidinic endonucleases (APE) will be protective from bleomycin-induce pulmonary toxicity and that methylguanine DNA methyltransferase (MGMT) will be protective from CENU induced toxicity. Both in vitro and in vivo studies are proposed. The hypothesis is: Augmentation of specific DNA repair proteins in lung cells will significantly reduce the toxicity of bleomycin or CENU. Specific aims include: 1) use viral or non-viral vectors to augment intracellular levels of DNA repair proteins in lung cell in vitro; 2) determine if augmentation of intracellular levels of DNA repair proteins in lung cells in vitro reduced lung cell toxicity from rugs (bleomycin, CENU, hyperoxia) in vitro; 3) determine if transgenic mice over-expressing DNA repair proteins in the lung are more resistant to toxicity from drugs (bleomycin, CENU, hyperoxia) in vivo; 4) determine if augmentation of DNA repair proteins in the lung by airway delivery of non-viral vectors reduces lung toxicity from drugs (bleomycin, CENU, hyperoxia) in vivo. If successful, this project will provide the experimental basis for protecting key lung progenitor cells form cytotoxic drug damage, thereby preserving the integrity of the alveolar capillary unit; and if injury occurs, permitting its cellular reconstitution by the protected lung cells undergoing normal compensatory replication and differentiation.

癌症化学治疗剂如博来霉素和 氯乙基亚硝基脲（CENU）与高发病率有关， 肺毒性这些药物引起的肺损伤和纤维化 代表了这些药物治疗功效的主要限制因素 治疗癌症的药物博莱霉素和CENU均会导致DNA损伤 通过包括产生脱嘌呤/脱嘧啶（AP）位点的机制， 链断裂和异常DNA加合物，导致细胞死亡。 细胞毒性药物的肺毒性通常与 肺毛细血管内皮损伤及I型和II型 肺泡上皮细胞该项目将侧重于具体的 DNA修复蛋白在保护肺细胞免受DNA损伤引起的 博莱霉素或CENU和高氧，一种与 药物性肺病加重。建议具体 DNA修复蛋白如脱嘌呤/脱嘧啶核酸内切酶（APE）将 保护免受博来霉素诱导肺毒性， 甲基鸟嘌呤DNA甲基转移酶（MGMT）将保护CENU 诱导毒性。提出了体外和体内研究。的 假设：肺细胞中特异性DNA修复蛋白的增加 将显著降低博莱霉素或CENU的毒性。具体目标 包括：1）使用病毒或非病毒载体来增加细胞内水平 DNA修复蛋白在体外肺细胞中的表达; 2）确定是否增强 体外肺细胞中DNA修复蛋白的细胞内水平 降低地毯（博莱霉素、CENU、高氧）对肺细胞的毒性， 体外; 3）确定转基因小鼠是否过表达DNA修复蛋白 在肺中对药物（博来霉素，CENU， 高氧）; 4）确定是否增加DNA修复蛋白， 通过气道递送非病毒载体的肺降低了肺毒性 体内药物（博来霉素、CENU、高氧）。如果成功，这 为保护关键肺提供实验依据 祖细胞形成细胞毒性药物损伤，从而保留 肺泡毛细血管单位的完整性;如果发生损伤，允许 受保护的肺细胞进行正常的细胞重建 补偿性复制和分化。