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.
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