Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orotic acid, first discovered in ruminant milk, is an intermediate in the pyrimidine biosynthesis pathway of animal cells. Its synthesis is initiated by the formation of carbamoyl phosphate (CP) in the cytoplasm, with ammonia derived from glutamine. Ureotelic species also form CP in the first step of urea synthesis in liver mitochondria. For that, ammonia is derived from tissue fluid. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, CP leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated, orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high with hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase. It is also elevated by ammonia intoxication and during feeding of diets high in protein, high in lysine with respect to arginine, or deficient in arginine, ornithine, and citrulline. Rats fed 1% orotic acid or diets deficient in urea-cycle amino acids develop fatty livers, which has not been demonstrated in other species. Humans consuming 6 g of orotic acid daily have not shown adverse effects. Rats fed 1% orotic acid or arginine-deficient diets also showed more and larger foci positive for gamma-glutamyl transpeptidase and more liver tumors after administration of carcinogens and partial hepatectomy. Orotic acid feeding was also associated with the tendency for development of larger mammary tumors induced by chemical carcinogens in rats and with development of urinary bladder calculi containing high concentrations of orotic acid in mice. Conditions that raise tissue orotic acid change purine-pyrimidine ratios. It is unknown whether tissue orotate concentrations play a role in the recently observed enhanced proliferation of cells in the colon of rats fed high-protein, high-fat diets or in the promotion of chemically induced colon cancer by intrarectal administration of ammonium acetate.
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PMID:Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance. 154 44

The human TP53 gene is a possible tumor suppressor since TP53 gene mutations are observed in greater than 70% of sporadic colorectal carcinoma DNAs. In genomic DNAs from seven colon cancer cell samples, a 405 base pair DNA fragment containing exon 5, intron 5, and exon 6 of the TP53 gene was amplified by polymerase chain reaction and analyzed for mutations. One sample [human colon cancer (HCC) 278] was found to have a TP53 mutation altering the amino acid glutamine 167 in exon 5. A deletion of 2 bases changed glutamine 167 (CAG) to alanine (GCA) and the resulting frame-shift produced an in-frame stop codon at amino acid 179. While the normal TP53 gene gives rise to a 53 kD protein, the estimated size of this mutant TP53 protein if expressed would be approximately 20 kD.
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PMID:Mutation in the TP53 gene in colorectal carcinoma detected by polymerase chain reaction. 195 96

1. Oxygen consumption was investigated in two cultured subpopulations of either undifferentiated (Glc+ cells) or differentiated (Glc- cells) HT29 colon cancer cells and in the corresponding isolated mitochondria. In Glc+ cells, a decrease of the respiration is induced by the presence of glucose (Crabtree effect), whereas it is not the case in Glc- cells. 2. The oxidative phosphorylation rate of Glc- mitochondria is found to be much higher than that of Glc+ mitochondria, due to a higher efficiency to oxidize glutamine, glutamate, 2-oxoglutarate, succinate or malate. 3. In both types of mitochondria, respiration can be supported by the ADP formed by adenylate kinase or nucleotide diphosphate kinase, and, although to a lesser extent in Glc- mitochondria, by hexokinase. 4. Glc+ cells are characterized by a low respiration capacity and a high glycolytic flux leading to the Crabtree effect. Glc- cells are characterized by a better correlation between a moderate glycolytic flux and a high respiratory capacity.
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PMID:Respiration of mitochondria isolated from differentiated and undifferentiated HT29 colon cancer cells in the presence of various substrates and ADP generating systems. 215 27

Effect of glutamine deprivation (GLN- medium) and of its replacement by 4mM ammonium chloride (GLN-/NH4+ medium) or by 4mM glutamate (GLN-/Gt+ medium) was studied on growth rate, morphology and metabolism of HT29 human colon cancer cells. Growth rates were modified as follows: at the first passage, growth of GLN- cells was strongly decreased (doubling time: 192 hr vs 32 hr in control cells grown in GLN+ medium); GLN-/NH4+ cells and GLN-/Gt+ cells were found to have doubling times of 72 and 70 hr, respectively. At the 8th passage, doubling times were decreased in all cases, being: 144 hr for GLN- cells, 60 hr for GLN-/NH4+ cells and 24 hr for GLN-/Gt+ cells, which indicates a capacity of adaptation of the cell-line to new culture conditions. GLN- cells and GLN-/NH4+ cells were found to exhibit an enterocytic type of differentiation (polarization of the cell layer with apical and cystic brush border and tight junctions); GLN-/Gt+ cells remained undifferentiated and comparable to control GLN+ cells. Glycogen level varied according to the phases of the culture, with a trend to lower level in glutamine deprived cells; glucose uptake and lactate production varied as a function of the medium composition and of the phases of the culture. At the 8th passage, all the glutamine deprived cells produced less lactate than control; GLN-/Gt+ cells were found to utilize less glucose than others.
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PMID:Effect of glutamine deprivation and glutamate or ammonium chloride addition on growth rate, metabolism and differentiation of human colon cancer cell-line HT29. 286 87

The concentrations of free amino acid and protein-bound amino acid in gastric and colon cancers and also in normal tissues were measured and compared in order to investigate the differences in amino acid metabolism between these cancers. The examined materials were 20 specimens of gastric cancer, with 20 specimens of normal gastric full-thickness layers and 11 specimens of normal gastric mucosal layers, as well as 16 specimens of colon cancer, with 12 specimens of normal full-thickness layers and 16 specimens of normal colon mucosal layers. The amino acid pattern in gastric cancer was more similar to that in the gastric full-thickness layer than the gastric mucosal layer. On the other hand, the pattern in colon cancer was more similar to the colon mucosal layer than the full-thickness layer of normal colon tissue. Comparison between gastric and colon cancers showed that almost all of the protein-bound amino acid levels in gastric cancer were significantly higher than in colon cancer, while, conversely, all of the free amino acid levels except for aspartate, glutamate and glutamine were significantly lower in gastric cancer than in colon cancer. Both in the stomach and colon, the aspartate and glutamate levels in cancer tissues were significantly higher than in normal full-thickness or mucosal layers.
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PMID:Increased aspartate and glutamate levels in both gastric and colon cancer tissues. 810 61

Mutations in genes that lie in the retinoblastoma pathway have been implicated in the pathogenesis of many tumor types. Two critical components that determine progression from G1 to S include p16/CDKN2A and CDK4. Alterations in p16/CDKN2A have been well documented in multiple cancers, including melanoma. However, changes in CDK4 are apparently more rare. Only two alterations, both at codon 24, have been identified in CDK4: an activating arginine-to-cysteine transition and a germ-line arginine-to-histidine substitution in one French kindred. In a survey of 20 neuroblastomas, 17 uncultured metastatic melanomas, 33 uncultured primary uveal melanomas, 8 colon cancer cell lines, and 20 primary colon cancer samples, we found no evidence of mutations in exon 2 of CDK4. From our cell lines derived from metastatic melanomas, we detected two alterations in the functionally critical exon 2 of CDK4: a lysine-to-glutamine transition at codon 22 and the arginine-to-histidine mutation at codon 24. These findings document several novel changes in the p16-binding region of CDK4.
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PMID:Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. 942 66

Nutrition can control gastrointestinal (GI) tract growth at many stages of development. Fetal growth of the GI tract can be inhibited by restriction of the maternal diet, decrease of blood supply to the placenta, or partial obstruction of amniotic fluid swallowing. In most species there is an immature appearance of the GI mucosa that is characterized by large, long villi extending into the proximal colon. This pattern usually changes around the time of weaning and can be modified by manipulation of the diet. While total nutrition has a profound effect on GI development, there are specific nutrients that influence the epithelium during adult life. In the small intestine, glutamine has the most important effects and this amino acid is now considered conditionally essential. In the colon, dietary fiber has the strongest influence on mucosal structure and turnover. While it has been assumed that concentrations of bile acids and/or short chain fatty acids are the mediating factors, there is substantial evidence that mitigates against this conclusion. A better understanding of the molecular changes accompanying alterations in GI growth may lead to more comprehensive strategies for improving intestinal function and decreasing the risk of colon cancer.
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PMID:Nutritional regulation of gastrointestinal growth. 1007 94

The human Rad51 gene, HsRAD51, is a homolog of RecA of Escherichia coli and functions in recombination and DNA repair. BRCA1 and BRCA2 proteins form a complex with Rad51, and these genes are thought to participate in a common DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair. Additionally, we have shown that the pattern of northern blot analysis of the RadS gene is closely similar to those of the BRCA1 and BRCA2 genes. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancer. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. In both patients, blood DNAs showed a G-to-A transition in the second nucleotide of codon 150, which results in the substitution of glutamine for arginine. As this alteration was not present in any patients with breast or colon cancer examined, we assume that this missense alteration is likely to be a disease-causing mutation.
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PMID:Identification of Rad51 alteration in patients with bilateral breast cancer. 1080 37

We identified a novel type of point mutation at the 22nd codon of the K-ras gene in a primary colon cancer. The mutation was C to A transversion substituting lysine (AAG) for normal glutamine (CAG) codon. Biological activity of this mutant K-ras gene was tested by expression of full-length cDNA clones in NIH3T3 cells. Most of the K-ras Lys22-transfected cells exhibited an increased saturation density, a lower serum requirement, and transformed morphology reminiscent to the typical K-ras Val12 transformants. However, the tumorigenicity of K-ras Lys22 transformants in nude mice was significantly less potent than that of K-ras Val12 transformants; only a high copy number transformant produced tumors. Even though the activation is incomplete, the finding that the majority of tumor cells in the specimen carried the K-ras Lys22 mutation suggests that this mutation might be advantageous for growth of tumor cells in vivo.
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PMID:A novel activating mutation of the K-ras gene in human primary colon adenocarcinoma. 1109 64

L-asparaginase (EC 3.5.1.1) was purified to homogeneity from Thermus thermophilus. The apparent molecular mass of L-asparaginase was found to be 33 kDa by SDS-PAGE, whereas by Sephacryl S-300 superfine column it was found to be 200 kDa, indicating that the enzyme in the native stage acts as hexamer. It is a thermostable enzyme and keeps all of its activity at 80 degrees C for 10 min. The antiproliferative activity of the purified L-asparaginase from T. thermiphilus was tested against the following human cell lines: K-562 (chronic myelogenous leukemia), Raji (Burkitt's lymphoma), SK-N-MC (primitive neuroectodermal tumor), HeLa (cervical cancer), BT20 and MCF7 (breast cancers), HT-29 (human colon cancer), and OAW-42 (ovarian cancer). The antiproliferative activity of T. thermophilus enzyme was compared with Erwinase, the commercially available L-asparaginase from Erwinia corotovora. The potency difference between the two L-asparaginases was greater in HeLa and SK-N-MC than in other cell lines. The fact that L-asparaginase from T. thermophilus does not hydrolyse L-glutamine makes it advantageous for future clinical trials.
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PMID:Antitumor activity of L-asparaginase from Thermus thermophilus. 1126 87


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