Total parenteral nutrition (TPN) is an effective regimen for the repletion of malnutrition. The efficacy of TPN for the cancer patient, however, is complicated by the presence of the neoplasm. Results of animal studies demonstrate that TPN will accelerate tumor growth; biochemical results suggest that this may occur in man. Our recent results show that the plasma levels of arginine are correlated with tumor growth. An increase in plasma arginine and tumor growth occurs when TPN containing arginine is administered. Substituting ornithine for arginine in TPN does not affect plasma arginine levels as compared with the chow fed control. Tumor growth was also equal to the control. Erythrocyte putrescine, a measure of increased polyamine synthesis, was elevated after the administration of either arginine or ornithine. Although there was no correlation of polyamines with enhanced tumor growth, treatment with difluoromethylomithine (DFMO), a putrescine synthesis inhibitor, eliminates TPN-enhanced tumor growth. The experiments in this proposal are designed to evaluate the hypothesis that arginine is a limiting factor to the growth of the Ward colon tumor, fibrosarcoma, and a mammary tumor (13672-NF). A second hypothesis is that DFMO will improve the utilization of TPN-administered nutrients by the host. Fischer 344 rats with transplantable tumors growing subcutaneously will be used for all experiments. The relationship of arginine levels of plasma and tissues will be evaluated by giving TPN with essential and nonessential amino acids and adding arginine, ornithine, or citrulline at isonitrogenous and equimolar concentrations. Host nitrogen metabolism will be evaluated by measuring urine urea and ammonia excretion and measuring levels of amino acids and polyamines in liver, spleen, kidney, and skeletal muscle. Tumor protein and DNA synthesis and the time course of polyamine accretion will be compared with that of normal host tissue. Tumor proliferation will also be evaluated with Ki-67 immunostaining. In addition, the activities of arginase, glutaminase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, and polyamine acetylase enzymes of the tumor will be compared with that of the appropriate host tissues. The ability of ornithine to ameliorate DFMO-induced thrombocytopenia will be evaluated at specific molar ratios. The results of these experiments are expected to suggest a regimen for the cancer patient that will reduce the potential of TPN-enhanced tumor growth by formulation with ornithine in lieu of arginine and by reducing the DFMO-induced thrombocytopenia.
