INTERLEUKIN 10 AND BREAST CANCER THERAPY

白细胞介素 10 和乳腺癌治疗

• 批准号: 6173789
• 负责人: Amy M. Fulton
• 金额: $ 27.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173789
• 关键词: SCID mouse; antisense nucleic acid; apoptosis; athymic mouse; biological response modifiers; breast neoplasms; drug screening /evaluation; gene expression; gene induction /repression; gene targeting; genetically modified animals; immunomodulators; in situ hybridization; interferon gamma; interleukin 10; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic growth; neutralizing antibody; nonhuman therapy evaluation; regulatory gene

DESCRIPTION: (Applicant's Abstract) The cytokine interleukin-10 (IL-10) has shown therapeutic potential in a preclinical model of breast cancer. IL-10 is well tolerated in human volunteers. Expression of IL-10 as a transgene is associated with immune activation. For example, IL-10-engineered tumor cells immunize mice against challenge with the parent tumor and lead to enhanced generation of nitric oxide, elevated natural killer activity and induction of cell death. For each activity, the actions of IL-10 were indirect and dependent on the presence of interferon-gamma (IFN-gamma). IL-10 expression also results in the induction of the IFN-gamma-regulated genes Mig-1 and Gbp-1/Mag-1. Mig-1 protein has antitumor activity against human lymphomas. This application will test the hypothesis that IFN-gamma, mig-1 and/or gbp-1 expression are critical to the expression of antitumor activity by IL-10. Specific Aim 1 will determine the role of IFN-gamma in IL-10 mediated tumor inhibition. Using IFN-gamma mutant mice as well as neutralizing IFN-gamma antibody, the contribution of IFN-gamma to tumor inhibition mediated by IL-10 will be determined. Specific Aim 2 will determine the role of mig-1 in the therapeutic response to IL-10. Several approaches including the use of mig-1 antisense and mig-1 overexpression will be used to evaluate the contribution of mig-1 to tumor inhibition. If antitumor activity is identified for mig-1, the mechanism of action will be determined. Specific Aim 3 will determine the role of gbp-1/mag-1 in the therapeutic response to IL-10. The effect of gbp-1 overexpression and gbp-1 antisense on IL-10 mediated tumor inhibition will be determined. Specific Aim 4 will examine the role of IL-10 in control of human breast cancer. The effect of IL-10 overexpression on the growth and metastasis of human breast cancer cells will be determined. The role of mig-1 and gbp-1 will be examined in human tumors.

描述：（申请人的摘要）细胞因子白介素10（IL-10）具有 在乳腺癌的临床前模型中显示了治疗潜力。 IL-10 人类志愿者的容忍度很好。 IL-10作为转基因的表达 与免疫激活有关。 例如，IL-10工程肿瘤 细胞免疫小鼠免受父肿瘤的挑战，并导致 一氧化氮的产生增强，自然杀伤活动升高和 诱导细胞死亡。 对于每种活动，IL-10的动作是 间接和取决于干扰素 - 伽马的存在（IFN-gamma）。 IL-10表达也导致IFN-GAMMA调节的诱导 基因MIG-1和GBP-1/MAG-1。 Mig-1蛋白具有抗肿瘤活性 人淋巴瘤。 该应用将检验以下假设：IFN-Gamma， MIG-1和/或GBP-1表达对于抗肿瘤的表达至关重要 IL-10的活动。 具体目标1将决定IFN-Gamma在 IL-10介导的肿瘤抑制。 使用IFN-Gamma突变小鼠以及 中和IFN-gamma抗体，IFN-gamma对肿瘤的贡献 将确定由IL-10介导的抑制作用。 具体目标2将 确定MIG-1在对IL-10的治疗反应中的作用。 一些 方法包括使用MIG-1反义和Mig-1过表达 将用于评估MIG-1对肿瘤抑制的贡献。 如果 鉴定出用于MIG-1的抗肿瘤活性，作用机理将是 决定。 具体目标3将确定GBP-1/MAG-1在 对IL-10的治疗反应。 GBP-1过表达和GBP-1的影响 将确定对IL-10介导的肿瘤抑制的反义。 具体的 AIM 4将检查IL-10在控制人乳腺癌中的作用。 这 IL-10过表达对人乳房生长和转移的影响 将确定癌细胞。 MIG-1和GBP-1的作用将是 在人类肿瘤中检查。