AMINO ACIDS AND TUMOR GROWTH

氨基酸与肿瘤生长

• 批准号: 2097423
• 负责人: Bruce GROSSIE
• 金额: $ 16.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2097423
• 关键词: aminoacid metabolism; ammonia; arginine; breast neoplasms; citrulline; colon neoplasms; dietary aminoacid; difluoromethylornithine; enzyme activity; essential aminoacid; fibrosarcoma; laboratory rat; neoplasm /cancer nutrition therapy; neoplasm /cancer transplantation; neoplastic growth; nitrogen metabolism; nutrition aspect of cancer; nutrition related tag; ornithine; parenteral feedings; polyamines; thrombocytopenia; urea

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.

总肠胃外营养（TPN）是一种有效的方案 营养不良的补充。 TPN对癌症患者的功效， 但是，由于肿瘤的存在而变得复杂。 结果 动物研究表明，TPN将加速肿瘤的生长。 生化结果表明这可能发生在人中。 我们最近 结果表明，精氨酸的血浆水平与肿瘤相关 生长。 当TPN时，血浆精氨酸和肿瘤生长增加 含有精氨酸。 代替鸟嘌呤 与Chow相比，在TPN中不影响血浆精氨酸水平 美联储控制。 肿瘤生长也等于对照。红细胞 腐烂是多胺合成增加的量度，升高 给药精氨酸或鸟氨酸后。 虽然那里 多胺与肿瘤生长增强，治疗无关 与甲状腺蛋白合成抑制剂（DFMO）二氟甲基硫代氨酸（DFMO）， 消除了TPN增强的肿瘤生长。 该提案中的实验 旨在评估精氨酸是限制的假设 病房结肠肿瘤，纤维肉瘤和乳腺的生长因素 肿瘤（13672-NF）。 第二个假设是DFMO将改善 宿主利用TPN管理的营养素。 Fischer 344只大鼠 皮下生长的可移植肿瘤将用于所有人 实验。 血浆和组织的精氨酸水平的关系 将通过为TPN提供必需氨基的TPN来评估 酸和在异依性和 等摩尔浓度。 宿主氮代谢将通过 测量尿液尿素和氨排泄和测量氨基水平 肝，脾，肾脏和骨骼肌中的酸和多胺。 肿瘤蛋白和DNA合成以及多胺的时间过程 积聚将与正常宿主组织的增生进行比较。 瘤 还将通过KI-67免疫染色评估增殖。 在 补充，精氨酸酶，谷氨酰胺酶，鸟嘌呤的活性 脱羧酶，S-腺苷甲硫代氨酸脱羧酶和多胺聚胺 将肿瘤的乙酰酶与 适当的宿主组织。 鸟氨酸改善的能力 DFMO诱导的血小板减少症将以特定的摩尔比进行评估。 这些实验的结果有望暗示 癌症患者将降低TPN增强肿瘤的潜力 通过用鸟嘌呤代替精氨酸的配方生长并通过还原 DFMO诱导的血小板减少症。