Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fast-growing tumors are major glutamine consumers and may alter host glutamine metabolism to benefit the tumor. Previous studies from our laboratory have demonstrated that the liver switches from an organ of glutamine balance to one of glutamine release with progressive malignant growth. However, the regulation of this change is unclear. This study examined tumor modulation of hepatic glutamine metabolism by determining the activities of glutaminase, the principle enzyme of glutamine degradation, and glutamine synthetase, the principal enzyme of glutamine synthesis. Hepatic glutamine content was also determined. Rats with a fast-growing subcutaneous fibrosarcoma (TBR) and pair-fed controls were studied at 2 and 3 weeks after tumor or sham implantation, when the tumors comprised approximately 5% and 20% of total body weight. Arterial glutamine fell with progressive tumor growth (608 +/- 26 mumol/L in controls vs 494 +/- 15 in TBR, p less than 0.005) and was not attributable to a diminished food intake. Hepatic glutamine content was increased 45% (p less than 0.01) in tumor rats at 2 weeks due in part to a 35% fall in liver glutaminase activity. At 3 weeks, glutamine synthetase activity increased by 43% (0.58 +/- 0.07 mumol/mg of protein/hr in controls vs 0.83 +/- 0.04 in TBR, p less than 0.01) whereas glutaminase remained depressed (2.68 +/- 0.12 mumol/mg of protein/hr in controls vs 2.22 +/- 0.15 in TBR, p less than 0.05) and glutamine content fell compared to 2 week tumor-bearing rats, consistent with accelerated hepatic glutamine release. Tumors may alter liver glutamine metabolism by modulating hepatic enzyme activity in order to provide circulating glutamine for the growing malignancy.
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PMID:Tumor regulation of hepatic glutamine metabolism. 167 97

In vivo studies with L-[13N]glutamate in the Walker 256 carcinosarcoma implanted under the renal capsule of female Sprague-Dawley rats demonstrate that uptake of glutamate and the rate of incorporation of the nitrogen label from this amino acid into metabolites is slower in the tumor than in nontumorous kidney tissue. Glutamate dehydrogenase, glutaminase, and alanine aminotransferase activities are significantly lower within the tumor than within the adjoining kidney. However, the tumor expresses high levels of aspartate aminotransferase, attesting to the importance of this enzyme in the metabolism of glutamate. Indeed, high performance liquid chromatographic analysis showed that the principal metabolic fate of label derived from L-[13N]glutamate in the tumor is incorporation into aspartate. Measurement of specific activity ratios of glutamate to aspartate shows that the transfer of nitrogen from glutamate to aspartate is rapid and that equilibration of label among components of the aspartate aminotransferase reaction is attained within minutes after tumor uptake. Analyses of the nontumorous portion of the implanted kidney also showed that aspartate is the major recipient of glutamate nitrogen. However, high performance liquid chromatographic analyses of deproteinized tissue revealed that glutamine and ammonia are also significant 13N-labeled metabolites formed from L-[13N]glutamate within the kidney. Proportionately lower amounts of these labeled metabolites were found in the tumor.
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PMID:Short-term metabolic fate of L-[13N]glutamate in the Walker 256 carcinosarcoma in vivo. 197 67

Phosphate-dependent glutaminase activity in spleen, kidney, brain and liver is increased after tumor cell inoculation and this activity gradually increases with the progression of the tumor. The increase in enzyme activity in the liver is significant. Studies of the response of liver glutaminase after Cu-ATP treatment reveals that Cu-ATP is capable of reducing the high glutaminase level in subjects with malignant tumors to the normal level.
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PMID:Investigation on phosphate dependent glutaminase (EC 3.5.1.2) activity in host tissues of EAC-bearing mice and response of liver EC 3.5.1.2 on Cu-ATP therapy. 204 79

Glutamine is a principal fuel utilized by rapidly growing tumors. Advanced malignant disease results in muscle glutamine depletion and weight loss. Concern exists about providing dietary glutamine to the host with cancer since it may stimulate tumor growth. This study examined the effects of oral glutamine on muscle glutamine metabolism and tumor growth. Twenty-four rats with large sarcomas were pair fed a glutamine-enriched or glutamine-free elemental diet. Diets were isonitrogenous and isocaloric. After 6 days of feeding, the animals were anesthetized and arterial glutamine, hindquarter glutamine flux, muscle glutamine content, tumor weight, tumor DNA content, tumor glutaminase activity, and number of metaphase mitoses/high power field (HPF) in the tumor were determined. There was no difference in arterial glutamine between the two groups, but provision of a glutamine-enriched diet increased muscle glutamine content by 60% (2.31 +/- 0.21 mumole/g tissue vs 1.44 +/- 0.22 mumol/g tissue, P less than 0.05), which supported muscle glutamine release. There were no differences among tumor DNA content, tumor glutaminase activity, or tumor weight and there was no difference histologically in the number of metaphase mitoses/HPF. Glutamine-enriched oral diets may replete host glutamine stores and support muscle glutamine metabolism without stimulating tumor growth.
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PMID:Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. 233 17

Glutamine synthetase and glutaminase activities in a series of hepatoma cells of human and rat origins were determined for comparison with normal liver tissues. Marked decrease in glutamine synthetase activity was observed in the tumor cells. Phosphate-dependent and phosphate-independent glutaminase activities were increased compared with those from normal liver tissues. Well coupled mitochondria were isolated from HuH 13 line of human hepatoma cells and human liver. Oxypolarographic tests showed that glutamine oxidation was prominent in the tumor mitochondria, while mitochondria from the liver showed a feeble glutamine oxidation. Glutamine oxidation was inhibited by prior incubation of the mitochondria with DON (6-diazo-5-oxo-L-norleucine), which inhibited mitochondrial glutaminase. These results indicate that the product of glutamine hydrolysis, glutamate, is catabolized in the tumor mitochondria to supply ATP.
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PMID:Glutamine synthetase and glutaminase activities in various hepatoma cells. 257 54

The short-term metabolic fate of labeled nitrogen derived from [13N]ammonia or from L-[amide-13N]glutamine was determined in murine tumors known to be resistant (Ridgeway Osteogenic Sarcoma (ROS] or sensitive (Sarcoma-180 (S-180)) to glutaminase therapy. At 5 min after intraperitoneal injection of [13N]ammonia or of L-[amide-13N]glutamine, only about 0.7% of the label recovered in both tumors was in protein and nucleic acid. After [13N]ammonia administration, most of the label (over 80%) was in a metabolized form; a large portion of this metabolized label (50-57%) was in the urea fraction with a smaller amount in glutamine (37-42%). The major short-term fate of label derived from L-[amide-13N]glutamine was incorporation into components of the urea cycle with smaller amounts in the acidic metabolites and in acidic amino acids. No labeled urea was found during in vitro studies in which S-180 tumor slices were incubated with [13N]ammonia, suggesting that the [13N]urea formed in the tumor in the in vivo experiments was not due to de novo synthesis through carbamyl phosphate in the tumor. Both tumors exhibited very low glutamine synthetase activity. Following glutaminase treatment, glutamine synthetase and gamma-glutamyltransferase activities, while remaining low, increased in the resistant tumor but not in the sensitive tumor; this increase may be related to the insensitivity of the ROS tumor toward glutaminase treatment.
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PMID:[13N]Ammonia and L-[amide-13N]glutamine metabolism in glutaminase-sensitive and glutaminase-resistant murine tumors. 286 80

Twenty-four h after tumor transplantation increases of free glutamine in plasma, liver, and kidney occurred simultaneously with the exponential phase of tumor growth. Kidney and muscle glutamine synthetase also increased in the first 2 days following tumor transplantation, while kidney and liver glutaminases decreased. The levels of free glutamine in plasma and tissues, and the activities of glutamine synthetase and glutaminase, tended to approach normal values in the last days of life of the tumor-transplanted animals. Eleven days after transplantation, liver glutamine synthetase activity diminished. The results are discussed in terms of a glutamate/glutamine intercellular cycle which could augment the circulating glutamine, the main source of nitrogen for tumor cells.
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PMID:Contribution by host tissues to circulating glutamine in mice inoculated with Ehrlich ascites tumor cells. 289 41

Well coupled mitochondria were isolated from transplantable chicken hepatoma induced by MC-29 virus. The mitochondrial phosphate-dependent and phosphate-independent glutaminase activities were increased compared with those from normal chicken liver. Glutamate dehydrogenase was undetectable in the tumor mitochondria. Oxypolarographic tests showed the following: glutamine oxidation was prominent in the tumor mitochondria and was mediated through an NAD-linked reaction, while mitochondria from the liver showed a feeble glutamine oxidation; glutamine oxidation by tumor mitochondria was inhibited either by aminooxyacetate, inhibitor of transaminases, or prior incubation of mitochondria with DON (6-diazo-5-oxonorleucine), which inhibited mitochondrial glutaminases. Bromofuroate, inhibitor of glutamate dehydrogenase, had little or no effect; and glutamate oxidation was also inhibited by aminooxyacetate, while it was not affected by DON. These findings clearly show a high glutamate oxidation activity in the hepatoma and indicate that the product of glutamine hydrolysis, glutamate, is catabolized via transamination in the mitochondria to supply ATP.
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PMID:Prominent glutamine oxidation activity in mitochondria of avian transplantable hepatoma induced by MC-29 virus. 301 1

Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host. Tumour tissue slices showed a marked preference for glutamine, especially for oxidation of its skeleton to CO2. It is proposed that the metabolism of this particular carcinoma is focused on amino acid degradation, glutamine being its preferred substrate.
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PMID:Amino acid metabolism in tumour-bearing mice. 334 22

Forty-eight tumor-free mice and 32 mice bearing Ehrlich ascites tumor were randomized into 2 treatments, Acinetobacter glutaminase-asparaginase (AGA) (600 IU/kg/day for 7 days) and 0.9% NaCl controls, and into 2 or 3 isocaloric diets, normal protein (NP) (20 g protein/100 g diet), high protein (HP) (58 g protein/100 g diet), and zero protein (ZP) (tumor-free mice only). In tumor-free, NP-fed mice, AGA caused percentage reductions (P less than 0.01) in the nitrogen content of liver (50%), intestine (42%), thymus (89%), spleen (75%), and carcass (20%), but HP prevented this effect on intestine and carcass and caused percentage increases in the nitrogen content of liver (53%), intestine (36%), thymus (122%), and carcass (25%). In Ehrlich ascites tumor mice (NP or HP fed) AGA caused markedly lower (P less than 0.01) tumor burdens and increased nitrogen content of intestine (HP), kidney (NP and HP), and spleen (NP and HP). Ehrlich ascites tumor, AGA-treated, HP-fed mice ate 31% less food (P less than 0.01) (compared to NP) but HP resulted in percentage increases in the nitrogen content of liver (18%; P = 0.05), intestine (25%; P less than 0.05), and thymus (164%; P less than 0.01). In the Ehrlich ascites tumor, AGA group the HP diet caused higher hematocrit and serum total protein (both, P less than 0.05). Adverse nutritional effects of AGA seen in normal mice were markedly diminished in tumor-bearing animals. The observed nitrogen-sparing effects of the high protein: energy ratio may be relevant to humans and to other forms of neoplasia and chemotherapy.
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PMID:Tissue nitrogen-sparing effect of high protein diet in mice with or without ascites tumor treated with Acinetobacter glutaminase-asparaginase. 402 74


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