HYPERAMMONEMIA AND CANCER ANOREXIA

高氨血症和癌症厌食症

基本信息

批准号：
3191987
负责人：
WILLIAM T CHANCE
金额：
$ 11.81万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-05 至 1991-06-30
项目状态：
已结题

项目摘要

Anorexia is a common problem of neoplastic disease that limits aggressive therapy of cancer and increases the morbidity and mortality of the disease. Although many hypotheses of cancer anorexia have been advanced, the complexity of physiologic controls of feeding and satiety have precluded resolution of this problem. Since cancer anorexia appears to be due to remote effects of a tumor that are disseminated humorally, any integrative theory must consider the interaction of peripheral biochemical aberrations with brain mechanisms of feeding and satiety. Results from studies of experimental cancer suggest that large quantities of glucose and amino acids are removed from circulating blood by the tumor mass. The amino acid, glutamine, appears to be particularly important for tumor metabolism, since blockade of glutamine metabolism effectively reduced tumor growth. The major products of tumor metabolism appear to be lactic acid and ammonia. Recent studies demonstrated a 3-fold elevation in blood ammonia concentration in anorectic tumor- bearing (TB) rats and a 10-fold increase in ammonia concentration in blood draining the tumor mass. Ammonia intoxication produces anorexia and elevations in brain glutamine, large neutral amino acids and amine neurotransmitters that are similar to changes observed in anorectic TB rats. Therefore it is hypothesized that the increased ammonia concentrations in the blood and brain and the neurochemical aberrations induced by the detoxification of ammonia in the brain area very important factors in the development of cancer anorexia. This hypothesis will be tested by: (1) determining the temporal relationship between alterations in blood and brain ammonia on the onset of anorexia in TB rats; (2) assessing the effects of ammonia infusions in normal rats on food intake and neurochemistry; (3) measuring the increase in CSF glutamine as anorexia develops using intraventricular push-pull perfusion of TB rats; (4) assessing the anorectic effects in the intraventicular adminstration of glutamine to normal rats; (5) determining the effects of a glutamine synthetase inhibitor on cancer anorexia; (6) assessing whether infusion of arginine and citrulline will aid in host detoxificiation of ammonia and reduce the anorexia; (7) exploring dietary changes that reduce glutamine and the increased neutral amino acid concentrations in the brain as treatments for anorexia; and (8) determining whether blood ammonia concentrations are elevated in anorectic cancer patients. These experiments should delineate specific causes of anorexia in cancer and suggest several therapeutic options.

厌食症是肿瘤疾病的常见问题对癌症的积极治疗，增加了发病率和疾病的死亡率。尽管许多癌症的假设厌食症已经提高了，生理的复杂性喂食和饱腹感的控制无法解决问题。由于癌症厌食似乎是由于偏远肿瘤的效果被幽默地传播综合理论必须考虑周围的相互作用具有喂食和大脑机制的生化畸变和饱腹感。实验癌研究的结果表明从中除去大量的葡萄糖和氨基酸肿瘤质量循环血液。氨基酸，谷氨酰胺，似乎对肿瘤代谢特别重要，因为阻断谷氨酰胺代谢有效减少了肿瘤生长。肿瘤代谢的主要产物似乎是乳酸和氨。最近的研究表明有3倍肛门肿瘤中血液氨浓度的升高 - 轴承（TB）大鼠氨浓度增加10倍在肿瘤质量中排出血液。氨中毒会产生脑谷氨酰胺的厌食和高程，大型中性氨基与变化相似的酸和胺神经递质在厌食性结核病大鼠中观察到。因此，假设血液和大脑中氨浓度的增加，以及由解毒引起的神经化学畸变大脑区域的氨非常重要的因素癌症厌食症的发展。该假设将进行检验作者：（1）确定改变之间的时间关系在结核病大鼠厌食症发作的血液和脑氨中；（2）评估正常大鼠氨输注对食物摄入和神经化学；（3）测量CSF的增加麸结核大鼠的灌注；（4）评估在谷氨酰胺对正常大鼠的静脉内刺激性；（5）确定谷氨酰胺合成酶抑制剂对癌症厌食症；（6）评估精氨酸和瓜氨酸将有助于宿主对氨的排毒并减少厌食症；（7）探索减少谷氨酰胺的饮食变化和大脑中的中性氨基酸浓度增加作为厌食症的治疗；（8）确定是否血液氨浓度升高患者。这些实验应描述癌症中的厌食症，并提出了几种治疗选择。