INFLUENCE OF BIOPERIODICITY ON TUMOR IMMUNOTHERAPY

这项研究的目的是确定宿主的昼夜节律 重组人肿瘤坏死因子、重组人白介素1β、环磷酰胺对肿瘤免疫治疗疗效的影响 亚致死剂量的伽马射线。众所周知，这些免疫调节剂可以诱导 通过增强或促进抗癌基因的表达而使肿瘤消退 而不是通过对肿瘤本身的直接影响。此外, 这些制剂中的每一种都只与免疫系统接触了很短的时间 时间到了。据推测，最小治疗剂量的疗效 这些免疫调节剂将以昼夜节律依赖的方式变化 由于(A)免疫调节剂的清除率不同 来自血液和/或(B)反应性的差异或 不同时间靶组织对免疫调节剂的敏感性。 实验最初将被设计来确定是否存在 两组治疗效果差异有统计学意义 这些免疫调节剂在不同时间给药的免疫治疗 昼夜节律。每种药物都将在#年进行时间生物学评估 在一年中的三个不同时间进行年龄匹配的小鼠，以建立 节律参数的重复性和检测潜在的昼夜节律 节奏。更多的实验将集中在那些具有 统计证实了昼夜节律在治疗效果中的作用 确定治疗活性的昼夜节律变化是否 免疫调节剂是由影响血清的生理节律引起的。 该制剂在荷瘤宿主中的半衰期。已发布的程序 将使用检测体液中的肿瘤坏死因子、白介素1和环磷酰胺。此外，这些 可以对试剂进行放射性标记，以便监测昼夜节律 它们的组织分布、代谢和/或排泄的变化。 通过调整肿瘤坏死因子、白介素1β、环磷酰胺或伽玛射线的给药 为了托管生物节律，有可能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 肿瘤免疫治疗的疗效。这种方法的成功将取决于， 然而，关于使用适当的免疫介导性肿瘤模型 关于存在哪些关于贡献的知识的回归 治疗时对宿主免疫的正负调节。

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.