CHRONOBIOLOGICAL INVESTIGATION OF TNF AND IL-2

TNF 和 IL-2 的时间生物学研究

基本信息

批准号：
3195411
负责人：
WILLIAM JM HRUSHESKY
金额：
$ 9.14万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-07-06 至 1994-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3195411
关键词：
albino mouse animal population study antineoplastic antibiotics cellular immunity chronotherapy circadian rhythms drug adverse effect immunopharmacology interleukin 2 metastasis neoplasm /cancer immunotherapy neoplasm /cancer transplantation nonhuman therapy evaluation pituitary adrenal axis seasons sex cycle tumor necrosis factor alpha

项目摘要

It is proposed to investigate the circadian stage dependency of the toxicities, biologic activities and anticancer activities of recombinant human Tumor Necrosis Factor (rhTNF) and Interleukin 2 (rhIL-2) in the Balb/c mouse with and without an implanted Meth-A sarcoma. We have found preliminarily that the circadian time and season of tumor inoculation affect both tumor take rate and natural killer cell activity. We have also found that the timing of tumor resection within the fertility cycle affects the frequency of subsequent metastatic tumor spread and that the fertility cycle affects the level of immunocyte NK activity. Therefore, the effects of female fertility cycle stage and season at time of study will also be quantified. The biological effects of most, if not all, trophic hormones are dependent to some extent upon the temporal patterning of their release or administra- tion. Fertility depends upon the pulsatility of FSH and LH delivery from the pituitary to the ovary and testis. Cortisol release depends intimately upon both the high frequency pulsing and the circadian patterning of ACTH delivery from the pituitary to the adrenal glands. IL-1 is a centrally positioned cytokine having synergistic activities with TNF and interactive or stimulatory effects upon several other cytokines and growth factors. Glucocorticoids (which are exquisitely circadian rhythmic) modulate the dynamics of IL-1 gene transcription rate, messenger RNA stability and resultant translation rate and IL-1 cellular release rate, as well as TNF- induced cytotoxicity. IL-1, in turn, modulates glucocorticoid receptor binding, decreases available binding sites and reduces steroid-associated enzyme induction. These steroid/cytokine interactions suggest that chronobiologic investigation of cytokine toxicity and anticancer efficacy may be important. The toxic and therapeutic anticancer effects of many cytotoxic xenobiotic anticancer agents depend upon their circadian timing. Reproducible peak- trough circadian differences in toxicity and anticancer activity usually range between 50% and 250%. Preliminary data on tumor necrosis factor indicate that the circadian stage dependent differences in toxic/therapeut- ic ratio may be of substantially higher magnitude for cytokines. Specific hypotheses to be addressed by the proposed research include: 1) Endogenous, reproducible, nontrivial and quantifiable circadian rhythms ( which are reproducibly modulated by both the fertility cycle and season) characterize (murine and human) normal biology; 2) Population synchrony, gauged by reference to sleep-wake schedules and physiologic circadian marker rhythms, may be used to extrapolate phase relationships appropriate- ly from individual and species to species; 3) Endogenous activity of natural immunologic defense networks have rhythmic circadian, fertility cycle and seasonal variation; 4) The hypophyseal-adrenal network is an important circadian coordinator of cellular immune networks; 5) These networks have rhythmic circadian, fertility cycle and seasonal variation in their ability to be stimulated; 6) The circadian timing of TNF reproducibly affects its toxicity and its antitumor efficacy; 7) The circadian timing of IL-2 reproducibly affects its toxicity and its antitumor efficacy.

建议调查昼夜节律的依赖重组的毒性，生物活动和抗癌活性人类肿瘤坏死因子（RHTNF）和白介素2（RHIL-2）带有和没有植入的甲虫的BALB/C小鼠。我们找到了首先是肿瘤接种的昼夜节律时间和季节影响肿瘤的患病率和天然杀伤细胞活性。我们也有发现在生育周期内肿瘤切除的时机会影响随后的转移性肿瘤的频率扩散和生育能力循环影响免疫细胞NK活性的水平。因此，效果在学习时的女性生育周期阶段和季节也将是量化。大多数（如果不是全部）营养激素的生物学作用取决于在某种程度上，其释放或行政的时间模式 tion。生育能力取决于FSH和LH传递的脉动卵巢和睾丸的垂体。皮质醇释放密切取决于在高频脉冲和艾克斯的昼夜节律上从垂体到肾上腺的递送。 IL-1是一个中央定位具有与TNF和Interactive协同活性的细胞因子或对其他几种细胞因子和生长因子的刺激作用。糖皮质激素（精美的昼夜节律）调节 IL-1基因转录率，信使RNA稳定性和由此产生的翻译率和IL-1细胞释放速率，以及TNF- 诱导的细胞毒性。 IL-1反过来调节糖皮质激素受体结合，减少可用的结合位点并减少类固醇相关的酶诱导。这些类固醇/细胞因子相互作用表明细胞因子毒性和抗癌功效的时间生物学研究可能很重要。许多细胞毒性异生元的有毒和治疗性抗癌作用抗癌剂取决于他们的昼夜节律。可重复的峰 - 昼夜节日毒性和抗癌活性的差异通常范围在50％至250％之间。肿瘤坏死因子的初步数据表明昼夜阶段依赖于有毒/疗法的差异对于细胞因子，IC比可能具有更高的幅度。拟议的研究要解决的具体假设包括：1）内源性，可重现，非平地和可量化的昼夜节律（这是通过生育周期和季节可重复调节的）表征（鼠和人类）正常生物学； 2）人口同步，参考睡眠觉醒时间表和生理昼夜节律进行评估标记节奏可用于推断适当的相位关系 - 从个人和物种到物种； 3）内源性活性自然免疫防御网络具有节奏昼夜节律，生育能力周期和季节性变化； 4）垂体 - 肾上腺肾上腺网络是细胞免疫网络的重要昼夜节律协调员； 5）这些网络具有有节奏的昼夜节律，生育周期和季节性变化他们的刺激能力； 6）TNF的昼夜节律可重复影响其毒性及其抗肿瘤功效； 7）昼夜节律的时机 IL-2可重复影响其毒性及其抗肿瘤功效。