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)

Angiogenesis or the generation of new blood vessels, is an important factor regarding the growth of a tumor. Hence, it becomes a necessary parameter of any kind in therapeutic studies. Glutamine is an essential nutrient of tumor tissue and glutamine related therapy involves clearance of circulatory glutamine by glutaminase. So, whether this enzyme has any effect on angiogenesis of a tumor or not becomes an obvious question. To address this question, this study has been carried out with different murine tumor models. The results indicate that purified glutaminase reduces tumor volume as well as restricts the generation of new blood vessels. Glutaminase is effective in the case of solid as well as ascites tumor models. In the case of induced cancer, the host exhibits delayed onset of neoplasia following enzyme treatment and tumor host interactions determine the intensity of the neovascularisation process. Therefore, it can be concluded that this enzyme might be an effective agent against cancer metastasis.
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PMID:Angiogenesis a putative new approach in glutamine related therapy. 1060 27

High rate of glutamine use is a characteristic of tumor cell both in vivo and in vitro and experimental cancer therapies have developed by depriving tumor cells of glutamine. In several investigations, bacterial glutaminase was found to be a potent therapeutic agent against varieties of tumor, but it showed suppressive effects on haematopoietic systems and inhibitory effects on normal lymphocytic blastogenesis. No antineoplastic study has nevertheless been undertaken with glutaminase enzyme purified from mammalian source. In the present study we report the purification of glutaminase enzyme from mitochondria of highly malignant S-180 cell using ion exchange chromatography and affinity column chromatography of glutamine. Purified enzyme is a kidney type phosphate dependent glutaminase with Mr 64 KD. Effect of enzyme therapy has been investigated in transplantable as well as induced tumor model in both ascites and solid form. It has been observed that the enzyme at the total dose of 10 unit/mouse successfully inhibited the tumor burden both in ascitic and solid tumor and subsequently increases the host's life span. There was no significant toxic effect on the peripheral blood cells.
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PMID:Isolation and purification of phosphate dependent glutaminase from sarcoma-180 tumor and its antineoplastic effects on murine model system. 1074 73

Changes in the relative mRNA levels of phosphate-activated glutaminase (PAG) and glutamine synthetase (GS) in the liver and kidney of mice bearing a highly malignant strain of Ehrlich ascites tumor cells were determined at different days after tumor transplantation. Kidney glutaminase mRNA steadily increased, reaching maximum values at day 10 of tumor growth, while those of glutamine synthetase did not change, resulting in a sustained decrease of the GS/PAG ratio in the kidneys of tumor-bearing animals compared with controls. However, the GS/PAG ratio in the liver significantly increased, mainly due to a strong decrease in PAG, whereas GS mRNA levels remained almost unaffected. These results, combined with those previously reported on enzymatic activities and glutamine concentrations in the host-tumor system, suggest a long-term regulation of the host glutaminase enzymes in order to increase the circulating glutamine levels needed for tumor growth.
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PMID:Changes in mRNAs for enzymes of glutamine metabolism in the tumor-bearing mouse. 1092 57

Distribution of glutamine level in different tissues of tumor bearing mice such as brain, liver, kidney, spleen, large and small intestine and the tumor itself were studied in three solid tumor models, viz, Ehrlich ascites carcinoma, Sarcoma-180 and methylcholanthrene induced carcinoma. Tumor bearing mice were subjected to therapy for 7 days with the glutaminase purified from malignant S-180 cell. The results exhibit a significant decrease in tumor burden after enzyme therapy. Host tissue glutamine levels were significantly elevated in tumor bearing untreated mice in comparison to the normal ones, while significant lower values were obtained after enzyme therapy. It therefore appears that elevated levels of glutamine in host tissue are associated with the tumor burden.
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PMID:A general survey of glutamine level in different tissues of murine solid tumor bearing mice before and after therapy with purified glutaminase. 1096 12

The effect of L-glutamine (Gln) on mitochondrial glutathione (mtGSH) levels in tumor cells was studied in vivo in Ehrlich ascites tumor (EAT)-bearing mice. Tumor growth was similar in mice fed a Gln-enriched diet (GED; where 30% of the total dietary nitrogen was from Gln) or a nutritionally complete elemental diet (SD). As compared with non-tumor-bearing mice, tumor growth caused a decrease of blood Gln levels in mice fed an SD but not in those fed a GED. Tumor cells in mice fed a GED showed higher glutaminase and lower Gln synthetase activities than did cells isolated from mice fed an SD. Cytosolic glutamate concentration was 2-fold higher in tumor cells from mice fed a GED ( approximately 4 mM) than in those fed an SD. This increase in glutamate content inhibited GSH uptake by tumor mitochondria and led to a selective depletion of mitochondrial GSH (mtGSH) content (not found in mitochondria of normal cells such as lymphocytes or hepatocytes) to approximately 57% of the level found in tumor mitochondria of mice fed an SD. In tumor cells of mice fed a GED, 6-diazo-5-norleucine- or L-glutamate-gamma-hydrazine-induced inhibition of glutaminase activity decreased cytosolic glutamate content and restored GSH uptake by mitochondria to the rate found in EAT cells of mice fed an SD. The partial loss of mtGSH elicited by Gln did not affect generation of reactive oxygen intermediates (ROIs) or mitochondrial functions (e.g., intracellular peroxide levels, O(2)(-)(*) generation, mitochondrial membrane potential, mitochondrial size, adenosine triphosphate and adenosine diphosphate contents, and oxygen consumption were found similar in tumor cells isolated from mice fed an SD or a GED); however, mitochondrial production ROIs upon TNF-alpha stimulation was increased. Our results demonstrate that glutamate derived from glutamine promotes an inhibition of GSH transport into mitochondria, which may render tumor cells more susceptible to oxidative stress-induced mediators.
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PMID:Mitochondrial glutathione depletion by glutamine in growing tumor cells. 1106 16

Glutaminase (EC 3.5.1.2) is a key enzyme in rapidly proliferating cells. Using anti-sense technology, an Ehrlich ascites tumor cell line (0.28AS-2) with reduced glutaminase activity has been obtained. We investigated the in vivo growth characteristics of the 0.28AS-2 cells. When injected i.p. into normal Swiss albino mice, the 0.28AS-2 cells were unable to grow. On the contrary, when injected into nude mice, they developed into solid tumors. Mice inoculated with 0.28AS-2 cells kept immunologic memory and rejected a second inoculation with parental Ehrlich ascites tumor cells. Expression of both polymorphic epithelial mucin-1 (MUC-1) and the enzyme N-acetyl-alpha-D-galactosaminidase, proteins implicated in host immune system escape, were markedly diminished in 0.28AS-2 cells. Study of the immune system response in mice inoculated with 0.28AS-2 cells revealed an increase in splenic CD18 cells and the presence of a large number of activated F4/80+ macrophages in the ascites cavity. These features, not observed in mice inoculated with parental Ehrlich ascites tumor cells, indicate that a distinctive, strong immune response occurred in animals inoculated with 0.28AS-2 cells. Our results suggest that inhibition of glutaminase expression using anti-sense technology induces phenotypic changes in Ehrlich ascites tumor cells that allow the development of an effective anti-tumor immune response, which makes the cells unable to develop in vivo tumors.
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PMID:Ehrlich ascites tumor cells expressing anti-sense glutaminase mRNA lose their capacity to evade the mouse immune system. 1116 63

Angiogenesis or the generation of new blood vessel, is an important factor in the growth of a solid tumor. Hence, it becomes a necessary parameter of any kind of therapeutic study. Glutamine is an essential nutrient of tumor tissue and glutamine related therapy involves clearance of circulatory glutamine by glutaminase. Therefore, using different murine solid tumor models, the present study was undertaken to find out whether the S-180 cell glutaminase has any effect on angiogenesis of solid tumor, or not. Result indicates that the purified S-180 cell glutaminase reduces tumor volume and restrict the generation of neo blood vessels. Therefore, it can be concluded that this enzyme may be an effective device against the cancer metastasis.
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PMID:Neovascularisation offers a new perspective to glutamine related therapy. 1123 93

Glutamine is the major respiratory fuel and energy source of the rapidly proliferating tumor cells and that is why glutamine clearance by glutaminase therapy provides an opportunity to fight against the neoplasm. Glutaminase from bacterial source was tried on experimental models but had to be excluded because of its limited efficacy. Search for a better glutaminase continued exploiting the mammalian sources. In the present study, glutaminase purified from human ovarian cancer ascites fluid was used in experimental solid and ascites mice model alone and in combination with Cu-Sulphate and heparin. Cumulative findings indicate that the enzyme alone is quite effective in lowering tumor burden and reducing not only the tumor induced angiogenesis, but also an angiogenic inducer, heparin mediated angiogenesis. However, the presence of Cu with the enzyme, amplified the antineoplastic response by improving anti-angiogenic potential and hematological status of the tumor bearing host. Therefore, Cu-glutaminase combination strengthened the hypothesis that together they may provide a better therapeutic regimen in experimental mice tumor model.
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PMID:Effect of purified glutaminase from human ascites fluid on experimental tumor bearing mice. 1187 57

The protein content and the activity and type of phosphate-dependent glutaminase were determined in freshly pigmented lesions obtained from human melanoma and adjacent skin. Significant phosphate-dependent glutaminase activity was found in both the melanoma and non-pigmented adjacent skin areas. A comparison between the pigmented and adjacent skin areas suggests the occurrence of gradual metabolic changes that result in an increased protein content in the centre of the neoplasia. The presence of a kidney-type glutaminase (K(m) of 2-5 mm) indicates a high sensitivity of the melanoma to variations in glutamine plasma levels (0.6 to 1 mm). These data lead us to postulate that glutamine supply is an important factor for melanoma cell proliferation, being a source of nitrogen for DNA and RNA synthesis. The intense neovascularization observed in melanoma ensures the oxygen supply that is required for glutamine oxidation. These findings support the proposition that glutamine is an important fuel for melanoma.
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PMID:Human cutaneous melanoma expresses a significant phosphate-dependent glutaminase activity: a comparison with the surrounding skin of the same patient. 1257 26

Tumor cells expressing antisense glutaminase RNA show a drastic inhibition of glutaminase activity and they acquire a more differentiated phenotype. We have studied the expression of Sp1 and Sp3 transcription factors in both Ehrlich tumor cells and their derivative 0.28AS-2 antisense glutaminase expressing cells. The expression of phosphorylated Sp1 in 0.28AS-2 cells was 3-fold the expression in EATC. Full length Sp3 was also incremented in 0.28AS-2 cells. Sp1 and Sp3 binding to a consensus Sp1 probe was higher in 0.28AS-2 nuclear extracts, as determined by supershift assays. Sp1-DNA binding was inhibited by phosphatase treatment, demonstrating that phosphorylation of Sp1 is critical for its DNA binding capacity. The Sp1 and Sp3 DNA binding found in 0.28AS-2 cells was also correlated with an increased Sp1 activity, as shown in transient transfections assays carried out with a luciferase reporter plasmid. Incubation of Ehrlich tumor cells with the differentiation agent PMA could not totally reproduce the Sp1/Sp3 changes observed in 0.28AS-2 cells. However, it was demonstrated that the intracellular concentration of glutamine, but not glutamate or aspartate, is increased in 0.28AS-2 cells. In conclusion, the antisense inhibition of glutaminase leads to an increased expression of phosphorylated Sp1 and that correlates with an increase in Sp1 activity.
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PMID:Inhibition of glutaminase expression increases Sp1 phosphorylation and Sp1/Sp3 transcriptional activity in Ehrlich tumor cells. 1563 44


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