INFLUENCE OF BIOPERIODICITY ON TUMOR IMMUNOTHERAPY

生物周期性对肿瘤免疫治疗的影响

• 批准号: 3195504
• 负责人: EARL S DYE
• 金额: $ 6.11万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-13 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3195504
• 关键词: antineoplastics; chronotherapy; circadian rhythms; combination cancer therapy; cyclophosphamide; disease /disorder model; enzyme linked immunosorbent assay; gamma radiation; host neoplasm interaction; immunomodulators; interleukin 1; laboratory mouse; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; tumor necrosis factor alpha

The objective of this study is to determine whether host circadian rhythms influence the efficacy of tumor immunotherapy with rTNF, rIL-1beta, CY, or sublethal gamma-irradiation. These immunomodulators are known to induce tumor regression by enhancing, or facilitating, the expression of antitumor immunity rather than by a direct effect on the tumor itself. In addition, each of these agents is in contact with the immune system for only a short time. It is hypothesized that the efficacy of a minimum therapeutic dose with these immunomodulators will vary in a circadian-dependent fashion because of (a) differences in the rate of clearance of the immunomodulator from the blood and/or (b) differences in the responsiveness or susceptibility of target tissues to the immunomodulator at different times. Experiments will be designed initially to determine whether there are statistically significant differences in the therapeutic efficacy of immunotherapy with these immunomodulators given at different times during the circadian cycle. Each agent will be evaluated chronobiologically in age-matched mice at 3 different times during the year in order to establish reproducibility of rhythm parameters and to detect potential circannual rhythms. Additional experiments will focus on those agents with statistically verified circadian rhythms in therapeutic efficacy, to determine whether circadian-dependent variation in therapeutic activity of the immunomodulator is due to physiologic rhythms that influence the serum half-life of the agent in a tumor-bearing host. Published procedures for measuring TNF, IL-1 and CY in body fluids will be used. In addition, these agents can be radiolabeled in order to monitor circadian-determined variations in their tissue distribution, metabolism, and/or excretion. By tailoring the administration of TNF, IL-1beta, CY or gamma-irradiation to host biorhythms it may be possible to optimize the effect of these immunomodulators on antitumor effectors or suppressors and to improve the efficacy of tumor immunotherapy. The success of this approach will depend, however, on the use of appropriate models of immunologically mediated tumor regression about which knowledge exists concerning the contributions of positive and negative regulation on host immunity at the time of treatment.

本研究的目的是确定宿主的昼夜节律是否 影响rTNF、rIL-1 β、CY或 亚致死剂量的伽马射线照射 已知这些免疫调节剂诱导 通过增强或促进抗肿瘤基因的表达， 而不是直接作用于肿瘤本身。 此外，本发明还提供了一种方法， 这些药剂中的每一种都与免疫系统接触很短时间 时间 据推测，最小治疗剂量的疗效 这些免疫调节剂的作用将以昼夜节律依赖的方式变化 由于（a）免疫调节剂的清除速率的差异 和/或（B）反应性的差异，或 靶组织在不同时间对免疫调节剂的敏感性。 实验最初将被设计来确定是否有 治疗效果的统计学显著差异 免疫治疗期间的不同时间给予这些免疫调节剂 生理周期 每种药物将在以下时间进行时间生物学评价： 年龄匹配的小鼠在一年中的3个不同时间，以建立 节律参数的再现性和检测潜在的周期性 节奏 额外的实验将集中在那些代理与 统计学验证的治疗效果的昼夜节律， 确定是否昼夜节律依赖性变化的治疗活性， 免疫调节剂是由于影响血清的生理节律 在荷瘤宿主中的半衰期。 公布的程序， 将使用测量体液中的TNF、IL-1和CY。 另外这些 试剂可以被放射性标记以监测昼夜节律确定的 其组织分布、代谢和/或排泄的变化。 通过调整TNF、IL-1 β、CY或γ射线的给药， 为了宿主生物节律，可以优化这些生物节律的效果， 免疫调节剂对抗肿瘤效应物或抑制物的作用，并改善免疫调节剂对抗肿瘤效应物或抑制物的作用。 肿瘤免疫治疗的疗效。 这种方法的成功将取决于， 然而，在使用适当的免疫介导的肿瘤模型时， 回归，关于知识存在的贡献， 治疗时对宿主免疫力的正向和负向调节。