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.

厌食症是肿瘤性疾病的常见问题，限制了癌症的积极治疗会增加发病率该疾病的死亡率。尽管许多关于癌症的假说厌食症已经进展，生理的复杂性对进食和饱腹感的控制阻碍了这一问题的解决问题。由于癌症厌食症似乎是由于远程肿瘤通过体液传播的影响，任何整合理论必须考虑外围因素的相互作用与大脑进食机制有关的生化畸变饱腹感。实验性癌症研究的结果表明大量的葡萄糖和氨基酸被去除通过肿瘤块循环血液。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肿瘤生长。肿瘤代谢的主要产物是乳酸和氨。最近的研究表明 3 倍肛门肿瘤血氨浓度升高患有结核病的大鼠和氨浓度增加 10 倍在血液中排出肿瘤块。产生氨中毒厌食症和脑谷氨酰胺、大中性氨基酸升高与变化相似的酸和胺神经递质在厌食结核病大鼠中观察到。因此假设血液和大脑中氨浓度增加，解毒引起的神经化学畸变氨在大脑区域中非常重要的因素癌症厌食症的发展。这个假设将被检验通过：（1）确定改变之间的时间关系血液和脑氨对结核病大鼠厌食症发作的影响； (2) 评估正常大鼠输注氨水对食物摄入和神经化学； (3)测量CSF的增加谷氨酰胺作为厌食症的发展使用脑室内推拉结核病大鼠的灌注； (4) 评估厌食效果正常大鼠脑室内注射谷氨酰胺； (5) 确定谷氨酰胺合成酶抑制剂对癌症厌食症； (6) 评估是否输注精氨酸和瓜氨酸将有助于宿主对氨的解毒并减少厌食症； (7)探索减少谷氨酰胺的饮食改变以及大脑中中性氨基酸浓度的增加作为厌食症的治疗方法； (8) 判断是否有血液肛门癌中氨浓度升高患者。这些实验应该描述具体的原因癌症中的厌食症并提出了几种治疗选择。