NUTRITIONAL DETERMINANTS OF PROTEIN METABOLISM

对肿瘤生长调控的认识 影响细胞增殖、细胞质生长和 细胞裂解是荷瘤哺乳动物充分治疗的关键。 这种调节可以在体内的组织水平上表征，如果 同时测量蛋白质的合成和分解。 后者(肿瘤蛋白分解)是复合体的功能 宿主防御机制。我们实验室的最新数据 表明肿瘤生长较快与发病率较低有关 蛋白质的分解。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，那么它也是必要的 为了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 (尤其是肿瘤坏死因子，TNF)被假设为 调节患者的几种代谢紊乱 癌症。重组肿瘤坏死因子在健康大鼠体内的应用 实验室增强的肌肉蛋白分解，从而提供了一种可能的 肿瘤生长调控与宿主蛋白的关系 新陈代谢。对这种交互的进一步理解是 优先考虑最近对“领养”的兴趣 “免疫疗法”在治疗多发性骨髓瘤中的作用 癌症。可以估计组织蛋白质分解的速度 体内示踪剂亮氨酸在细胞内的同位素稀释 如果该示踪剂在等离子体中的交换性为稳态 对细胞内游离氨基酸库进行了量化。假设一个 灌流受限模型中，这些估计是在 纸巾。计算出的合成速率的代数和 破裂情况与组织的实际比率一致 成长。因此，一定的治疗方法对肿瘤生长的影响 而宿主瘦身质量的重新分布可以从 同样的示踪剂实验。 这项提议的目的是澄清 亮氨酸从血浆转移到组织中的组织 灌流和细胞内运输。肿瘤/宿主亮氨酸动力学 将与肿瘤胸腺嘧啶核苷动力学和 与增长相关。这些数据将用于验证 组织蛋白质合成速率和蛋白质合成速率的估算模型 崩溃了。在模型验证之后，相对的 蛋白质合成和分解过程的重要性 与肿瘤生长和癌症恶病质的关系将是 下定决心。该模型将作为进一步评估的工具 营养和代谢因素之间的相互作用 宿主蛋白质代谢，与肿瘤生长。

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.