INTERLEUKIN 10 AND BREAST CANCER THERAPY

描述：(申请人摘要)细胞因子白介素10(IL-10) 在乳腺癌的临床前模型中显示出治疗潜力。IL-10 在人类志愿者中被很好地耐受。白介素10作为转基因载体的表达 与免疫激活有关。例如，IL-10工程肿瘤 细胞免疫小鼠免受母体肿瘤的攻击并导致 增加一氧化氮的生成，提高自然杀伤活性和 诱导细胞死亡。对于每个活动，IL-10的作用是 间接的和依赖于干扰素-γ(干扰素-γ)的存在。 IL-10的表达也导致了干扰素-γ调节的 基因Mig-1和GBP-1/Mag-1。MiG-1蛋白具有抗肿瘤活性 人类淋巴瘤。这个应用程序将检验这样的假设，即干扰素-γ， MiG-1和/或GBP-1的表达对抗肿瘤的表达至关重要 IL-10的活性。特异性靶点1将确定干扰素-γ在 IL-10介导的肿瘤抑制作用。使用干扰素-γ突变小鼠以及 中和干扰素-γ抗体，干扰素-γ对肿瘤的贡献 IL-10介导的抑制作用将被确定。特定目标2将 确定MiG-1在IL-10治疗反应中的作用。几个 包括MiG-1反义和MiG-1过表达在内的方法 将用于评估MiG-1对肿瘤抑制的贡献。如果 MiG-1的抗肿瘤活性已确定，其作用机制将是 下定决心。具体目标3将确定GBP-1/MAG-1在 对IL-10的治疗反应。GBP-1过表达及其对GBP-1的影响 反义IL-10介导的肿瘤抑制作用将被确定。特定的 目的4将研究IL-10在控制人类乳腺癌中的作用。这个 IL-10过表达对人乳腺生长和转移的影响 癌细胞将被确定。MIG-1和GBP-1的作用将是 在人类肿瘤中进行检查。

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.