NUTRITIONAL DETERMINANTS OF PROTEIN METABOLISM

了解肿瘤生长的调控 影响细胞增殖、细胞质生长和 细胞裂解是对携带肿瘤的哺乳动物进行充分治疗的关键。 这种调节可以在体内在组织水平上表征， 同时测量蛋白质合成和分解。 后者（肿瘤蛋白分解）是复合物的功能 宿主的防御机制 我们实验室的最新数据 表明生长较快的肿瘤 蛋白质分解。 如果宿主介导的肿瘤蛋白分解 在调节肿瘤生长方面很重要， 描述和理解这一过程在 癌症恶病质的病理生理学。 一类单核细胞因子 （特别是肿瘤坏死因子，TNF）被假设为 介导患者的几种代谢紊乱， 癌 重组肿瘤坏死因子在健康大鼠体内的应用 实验室增强肌肉蛋白水解，从而提供了一种可能的 肿瘤生长调节与宿主蛋白的联系 新陈代谢. 对这种相互作用的进一步理解是 考虑到最近对“收养”的兴趣， 免疫疗法”在治疗患者的各种 癌的 组织蛋白质分解的速率可以估计 从同位素示踪亮氨酸的细胞内稀释 稳态，如果这种示踪剂在血浆中的交换率与 对游离的细胞内氨基酸库进行定量。 假设 灌注限制模型，这些估计是在不断增长的 组织中 计算合成速率的代数和 分解与组织的实际比率一致 增长 因此，某种治疗对肿瘤生长的影响 和宿主瘦体重再分布可以从 相同的示踪剂实验。 本提案的目的是澄清以下关系： 亮氨酸从血浆转移到组织中 灌注和细胞内转运。 肿瘤/宿主亮氨酸动力学 将与肿瘤胸苷动力学同时研究， 与增长相关。 这些数据将用于验证 用于估计组织蛋白质合成速率的模型， 崩溃 在模型验证之后，相对 蛋白质合成和分解过程在 与肿瘤生长和癌症恶病质的关系 测定 该模型将作为进一步评价的工具 营养和代谢因素之间的相互作用， 宿主蛋白质代谢和肿瘤生长。

The understanding of regulation of tumor growth through processes which affect cell proliferation, cytoplasmic growth, and cell lysis is key to adequate therapy in tumor-bearing mammals. This regulation can be characterized in vivo at the tissue level if protein synthesis and breakdown are simultaneously measured. The latter (tumor protein breakdown) is a function of the complex of host defense mechanisms. Recent data from our laboratory show that faster growing tumors are associated with lower rates of protein breakdown. If host-mediated tumor protein breakdown is important in regulating tumor growth, it is then also necessary to characterize and understand the role of this process in the pathophysiology of cancer cachexia. A class of monokines (especially tumor necrosis factor, TNF) is hypothesized to mediate several metabolic derangements in the patient with cancer. Administration of recombinant TNF to healthy rats in our laboratory enhanced muscle proteolysis, thus providing a possible link between tumor growth regulation and host protein metabolism. Further understanding of this interaction is a priority in view of the recent interest in "adoptive immunotherapy" in the treatment of patients with a variety of cancers. The rate of tissue protein breakdown can be estimated in vivo from the intracellular dilution of tracer leucine at isotopic steady state if the exchangeability of this tracer in plasma with the free intracellular amino acid pool is quantified. Assuming a perfusion-limited model, these estimates were made in growing tissues. The algebraic sum of the calculated rates of synthesis and breakdown was congruent with the actual rate of tissue growth. Thus, the effect of a certain treatment on tumor growth and host lean body mass redistribution can be predicted from the same tracer experiment. The goal of this proposal is to clarify the relationship between leucine transfer from plasma into tissues in terms of tissue perfusion and intracellular transport. Tumor/host leucine kinetics will be studied simultaneously with tumor thymidine kinetics and correlated with growth. These data will be used to validate a model for estimation of the rates of tissue protein synthesis and breakdown. Following validation of the model, the relative importance of the processes of protein synthesis and breakdown in relationship to tumor growth and cancer cachexia will be determined. The model will serve as a tool for further evaluation of the interaction between nutritional and metabolic factors with host protein metabolism, and tumor growth.