ANTICANCER DRUG RESISTANCE BY BCL-2 ONCOGENE EXPRESSION

BCL-2 癌基因表达的抗癌药物耐药性

• 批准号: 2429875
• 负责人: RAYMOND E MEYN
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429875
• 关键词: animal genetic material tag; antineoplastics; antioxidants; antisense nucleic acid; apoptosis; biological signal transduction; buthionine sulfoximine; drug resistance; free radical oxygen; gene expression; glutathione; human genetic material tag; ionizing radiation; mitochondria; oligonucleotides; oncogenes; polymerase chain reaction; protein structure function; thiols; tissue /cell culture; transfection /expression vector

DESCRIPTION: This proposal is aimed at evaluating the hypothesis that bcl-2 inhibition of apoptosis is mediated by increased levels of glutathione (GSH). The LY-as lymphoma cell line, which readily undergoes apoptosis in response to chemotherapeutic agents and ionizing radiation, will be transfected with bcl-2 under control of the inducible lac promoter. Antisense phosphorothioate oligonucleotides will be used to reduce bcl-2 expression in the LY-ar cell line which expresses high levels of bcl-2 and is resistant to induction of apoptosis. The relationship between GSH levels and apoptosis will be characterized in both systems. The mechanisms responsible for higher levels of GSH in cells resistant to apoptosis will be delineated and the role of reactive oxygen species (ROS) as mediators of apoptosis and GSH scavenging will be further defined. Animal models using the LY-as and LY-ar cell lines will be used to evaluate strategies with buthionine sulfoximine (BSO) to lower GSH to increase sensitivity to apoptosis.

描述：该提案旨在评估以下假设： bcl-2对细胞凋亡的抑制是通过增加bcl-2水平来介导的 谷胱甘肽（GSH）。 LY-as 淋巴瘤细胞系，在 对化疗药物和电离辐射的反应 在诱导型 lac 启动子的控制下用 bcl-2 转染。 反义硫代磷酸寡核苷酸将用于减少 bcl-2 在表达高水平 bcl-2 的 LY-ar 细胞系中表达 并且对细胞凋亡的诱导具有抵抗力。谷胱甘肽与谷胱甘肽的关系 水平和细胞凋亡将在两个系统中进行表征。这 细胞内谷胱甘肽水平升高的机制 将描述细胞凋亡和活性氧的作用 (ROS) 作为细胞凋亡和 GSH 清除的介质将进一步 定义的。将使用使用 LY-as 和 LY-ar 细胞系的动物模型 评估丁硫氨酸亚砜亚胺 (BSO) 降低 GSH 的策略 以增加对细胞凋亡的敏感性。