INTERLEUKIN 10 AND BREAST CANCER THERAPY

描述：（申请人的摘要）细胞因子白细胞介素-10（IL-10）具有 在乳腺癌的临床前模型中显示出治疗潜力。 IL-10 在人类志愿者中耐受性良好。 IL-10作为转基因的表达 与免疫激活有关。 例如，IL-10工程化肿瘤 细胞免疫小鼠对抗母体肿瘤的攻击， 一氧化氮的生成增加，自然杀伤活性升高， 诱导细胞死亡。 对于每种活性，IL-10的作用是 间接的并且依赖于干扰素-γ（IFN-γ）的存在。 IL-10的表达还导致IFN-γ调节的细胞凋亡的诱导。 Mig-1和Gbp-1/Mag-1基因。 Mig-1蛋白具有抗肿瘤活性， 人类淋巴瘤 本申请将检验IFN-γ， mig-1和/或gbp-1的表达对于抗肿瘤基因的表达是至关重要的。 IL-10的活性。 具体目标1将确定IFN-γ在以下方面的作用： IL-10介导的肿瘤抑制。 使用IFN-γ突变小鼠以及 中和IFN-γ抗体，IFN-γ对肿瘤的贡献 将测定由IL-10介导的抑制。 具体目标2将 确定mig-1在IL-10治疗反应中的作用。 几 包括使用MIG-1反义和MIG-1过表达的方法 将用于评价MIG-1对肿瘤抑制的贡献。 如果 鉴定了mig-1的抗肿瘤活性，作用机制将是 测定 具体目标3将确定gbp-1/mag-1在 对IL-10的治疗反应。 gbp-1过表达及gbp-1在肿瘤发生中的作用 将确定反义对IL-10介导的肿瘤抑制的影响。 具体 目的4将研究IL-10在人类乳腺癌控制中的作用。 的 IL-10过表达对人乳腺癌生长和转移的影响 将确定癌细胞。 米格-1和gbp-1的作用将是 在人类肿瘤中检测。

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.