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.

全肠外营养（TPN）是一种有效的治疗方案 补充营养不良。 TPN 对癌症患者的功效， 然而，肿瘤的存在使情况变得复杂。 结果 动物研究表明TPN会加速肿瘤生长； 生化结果表明这可能发生在人类身上。 我们最近的 结果表明血浆精氨酸水平与肿瘤发生相关 生长。 TPN 时血浆精氨酸增加和肿瘤生长 施用含有精氨酸的药物。 用鸟氨酸替代精氨酸 与食物相比，TPN 中的精氨酸不会影响血浆精氨酸水平 美联储控制。 肿瘤生长也与对照相同。红细胞 腐胺（多胺合成增加的衡量标准）升高 施用精氨酸或鸟氨酸后。 虽然有 多胺与增强肿瘤生长、治疗没有相关性 含有二氟甲基鸟氨酸（DFMO），一种腐胺合成抑制剂， 消除 TPN 增强的肿瘤生长。 本提案中的实验 旨在评估精氨酸是限制性的假设 沃德结肠肿瘤、纤维肉瘤和乳腺肿瘤生长的因素 肿瘤（13672-NF）。 第二个假设是 DFMO 将改善 宿主对 TPN 施用的营养物质的利用。 Fischer 344 大鼠 皮下生长的可移植肿瘤将用于所有 实验。 血浆与组织中精氨酸水平的关系 将通过给予 TPN 必需和非必需氨基酸来进行评估 酸并在等氮和添加精氨酸、鸟氨酸或瓜氨酸 等摩尔浓度。 宿主氮代谢将通过以下方式评估 测量尿素和氨排泄以及测量氨基水平 肝脏、脾脏、肾脏和骨骼肌中的酸和多胺。 肿瘤蛋白和DNA合成以及多胺的时程 将与正常宿主组织的增生进行比较。 瘤 增殖也将通过 Ki-67 免疫染色进行评估。 在 另外，精氨酸酶、谷氨酰胺酶、鸟氨酸的活性 脱羧酶、S-腺苷甲硫氨酸脱羧酶和多胺 肿瘤的乙酰化酶将与肿瘤的乙酰化酶进行比较 适当的宿主组织。 鸟氨酸的改善能力 DFMO 诱导的血小板减少症将在特定摩尔比下进行评估。 这些实验的结果有望提出一种治疗方案 癌症患者将降低 TPN 增强肿瘤的潜力 通过用鸟氨酸代替精氨酸配制并减少生长 DFMO 诱导的血小板减少症。