Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of oxygen on the quantitative histochemical assay to detect glucose-6-phosphate dehydrogenase (G6PDH) activity based on neotetrazolium reduction were studied in the different stages of carcinogenesis in the colon. Normal and hyperplastic epithelium, mucosae of patients with active Crohn's disease, and adenomas and adenocarcinomas of the colon were used. Epithelium of normal and inflamed mucosa, and hyperplastic epithelium, showed a residual G6PDH activity (RA) in oxygen that was always less than 20 per cent of the activity in the absence of oxygen. In adenomas and in dysplastic epithelia adjacent to carcinomas, the RA was significantly higher than that in normal epithelium, but significantly lower than that in adenocarcinomas. The RA of adenomas never exceeded 35 per cent. The RA of adenocarcinomas was on average 53 per cent and always higher than 20 per cent. When 35 per cent was used as a cut-off level, the sensitivity of RA to diagnose malignancy was 96.5 per cent. In a parallel study, a mouse model was used in which colon carcinomas and their precursors were induced chemically. Development of oxygen insensitivity during chemically induced carcinogenesis showed a pattern similar to that observed in the human. In conclusion, the test to determine RA is a useful tool for the detection of malignant mucosa in the colon. The test is particularly helpful in addition to histopathology for the detection of small lesions and the early stages of cancer.
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PMID:Development of oxygen insensitivity of the quantitative histochemical assay of G6PDH activity during colorectal carcinogenesis. 930 60

Kinetic parameters of glucose-6-phosphate dehydrogenase (G6PDH) and phosphogluconate dehydrogenase (PGDH) were determined in situ in livers of marine flatfish flounder that were caught in unpolluted areas in the open sea and in the highly polluted river Elbe (Germany). Analysis was performed quantitatively in liver sections using valid enzyme histochemical methods and image analysis. G6PDH but not PGDH was strongly affected by contaminant exposure and subsequent carcinogenesis. G6PDH showed a gradual decrease in Vmax and Km for glucose-6-phosphate in extralesional normal-looking liver tissue. Hepatocellular carcinomas also showed a low Km, whereas the Vmax was upregulated. These findings are interpreted as follows: prolonged challenges of the livers by pollutants inhibit or inactivate G6PDH and this is compensated for by reduction in Km. In carcinomas, G6PDH levels are upregulated but the low Km values are kept to increase the NADPH production capacity required in cancer cells showing that posttranslational regulation processes are important to control cellular metabolism under various environmental conditions.
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PMID:Adaptational changes in kinetic parameters of G6PDH but not of PGDH during contamination-induced carcinogenesis in livers of North Sea flatfish. 939 23

Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen. In this study we show that Fe-NTA is a potent inducer of renal ornithine decarboxylase (ODC) activity and DNA synthesis and promoter of N-diethylnitrosamine (DEN)-induced renal tumorigenesis in rat. Fe-NTA induced renal ODC activity several fold as compared with saline-treated rats. Renal DNA synthesis, measured as [3H]thymidine incorporation into DNA, was increased after Fe-NTA treatment. Similar to other known tumor promoters, Fe-NTA also depleted the antioxidant armory of the tissue. It depleted glutathione (GSH) levels to approximately 55% of saline-treated controls. It also led to a dose-dependent decrease in the activities of glutathione reductase and glutathione S-transferase. Similarly, activities of catalase, glutathione peroxidase and glucose 6-phosphate dehydrogenase decreased significantly (45-65%). In contrast, gamma-glutamyl transpeptidase activity showed an increase. The maximum changes in activities of these enzymes could be observed at 12 h following Fe-NTA treatment. In addition, Fe-NTA augmented renal microsomal lipid peroxidation >150% over saline-treated controls, which was concomitant with the alterations in GSH metabolizing enzymes and depletion of the antioxidant armory. These effects were alleviated in rats which received a pretreatment with an antioxidant, BHA or BHT. Fe-NTA promoted DEN-induced renal tumorigenesis. In saline alone- and DEN alone-treated animals no tumors could be recorded, whereas in Fe-NTA alone-treated animals 17% tumor incidence was observed. However, in DEN-initiated and Fe-NTA-promoted animals tumor incidence increased to 71%. Our results show that Fe-NTA induces oxidative stress in the kidney and decreases antioxidant defenses, as indicated by the fall in GSH level and in the activities of glutathione peroxidase and catalase. Concomitantly, Fe-NTA increases ODC activity and DNA synthesis, which may be compensatory changes following oxidative injury to renal cells in addition to providing a strong stimulus for renal tumor promotion. Thus oxidative stress and impaired antioxidant defenses induced by Fe-NTA in the kidney may contribute to the observed nephrotoxicity and carcinogenicity.
Carcinogenesis 1998 Jun
PMID:Ferric nitrilotriacetate promotes N-diethylnitrosamine-induced renal tumorigenesis in the rat: implications for the involvement of oxidative stress. 966 54

A significant depletion in the content of glutathione (GSH) and alteration in GSH redox system enzymes were observed in the lung of chrysotile-exposed animals (5 mg) during different developmental stages of asbestosis. In the alveolar macrophages (AM) of exposed animals, the depletion in GSH started from day 1 and reached a maximum at day 16, whereas in lung tissue the maximum depletion was observed when fibrosis has matured. It appears that cellular GSH depletion triggers oxidative stress in the system as observed from increased thiobarbituric acid reactive substance (TBARS) production and alteration in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PD) and glutathione S-transferase (GST), the enzymes regulating oxidative tone. The depletion in GSH was also observed in red blood cells (RBC) of the exposed animals reaching a maximum when fibrosis matured. Thus the observed depletion in GSH, ascorbic acid and alteration in GSH redox system enzymes may be involved in fibrosis and carcinogenesis induced by chrysotile.
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PMID:Chrysotile-mediated imbalance in the glutathione redox system in the development of pulmonary injury. 1037 48

With the passage of the U.S. Dietary Supplement Health and Education Act of 1994, dehydroepiandrosterone (DHEA, 5-androsten-3beta-ol-17-one) has become widely available, and a large and growing market has developed for this "fountain of youth." DHEA has been shown to have significant beneficial effects in animals, which may lead to clinical uses in man. Historically, the U.S. Food and Drug Administration removed DHEA from the over-the-counter market in 1985 because there was no support for the health claims that were made for this product. Almost all of the biological data was on animals and there was a lack of demonstrated efficacy in humans. Recently there have been a number of small clinical trials in humans but the results have not been as positive as in the animal tests. This review will be restricted to the effects of DHEA on carcinogenesis, obesity, the immune system, and aging. Four hypotheses have been proposed to explain the underlying biochemical mechanism(s) by which DHEA exerts its beneficial properties. The first is based on the inhibitory effect of DHEA on mammalian glucose-6-phosphate dehydrogenase. This mechanism can explain the antiinitiation and antipromotion steps in some cases of carcinogenesis. The second biochemical mechanism involves the induction of peroxisomes and peroxisome-associated enzymes. The third explanation is that DHEA works in a similar fashion to the known anticarcinogenic action of food restriction. An antiglucocorticoid mechanism has also been suggested. A hypothesis for the increase followed by the decrease in the levels of DHEA with age is proposed. A number of new synthetic DHEA analogs have been synthesized and tested. They offer the best hope for the development of a clinically useful drug based on the properties of DHEA.
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PMID:The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune system, and aging. 1078 10

Currently, one of the most popular applications of proteomics is in the area of cancer research. In Africa, Southeast Asia, and China, hepatocellular carcinoma is one of the most common cancers, occurring as one of the top five cancers in frequency. This project was initiated with the purpose of separating and identifying the proteins of a human hepatocellular carcinoma cell line, HCC-M. After two-dimensional gel electrophoresis separation, silver staining, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses, tryptic peptide masses were searched for matches in the SWISS-PROT and NCBI nonredundant databases. Approximately 400 spots were analyzed using this approach. Among the proteins identified were housekeeping proteins such as alcohol dehydrogenase, alpha-enolase, asparagine synthetase, isocitrate dehydrogenase, and glucose-6-phosphate 1-dehydrogenase. In addition, we also identified proteins with expression patterns that have been postulated to be related to the process of carcinogenesis. These include 14-3-3 protein, annexin, prohibitin, and thioredoxin peroxidase. This study of the HCC-M proteome, coupled with similar proteome analyses of normal liver tissues, tumors, and other hepatocellular carcinoma cell lines, represents the first step towards the establishment of protein databases, which are valuable resources in studies on the differential protein expressions of human hepatocellular carcinoma.
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PMID:Two-dimensional electrophoresis map of the human hepatocellular carcinoma cell line, HCC-M, and identification of the separated proteins by mass spectrometry. 1087 Sep 66

The ability to visualize the cellular effects of a somatic mutation is relevant to studies of cell kinetics and carcinogenesis. In the colon, mutagen administration leads to scattered crypt-restricted loss of activity of the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD); it has been shown that this is due to somatic mutation in the G6PD gene. Mutagen-induced crypt-restricted immunopositivity for metallothionein (MT) has been reported in one study in the mouse colon; if this is also due to somatic mutation, it provides a simple method for studying the phenomenon which could be carried out on paraffin sections. This study shows that, as in the G6PD model, the frequency of crypt-restricted immunopositivity for MT is very low in untreated animals, but increases proportionately with the dose of mutagen administered. There is a good overall correlation of a range of MT-positive crypt frequencies with those derived from studies using G6PD. As with the G6PD model, the MT-positive crypt phenotype evolves over time after mutagen administration; initially individual crypts include both positive and negative phenotype cells, but later almost all involved crypts are composed entirely of MT-positive cells. The frequency of MT-positive crypts stabilizes after a few weeks and remains at the same level 6 months later. All these observations are qualitatively identical to those found using the G6PD model and provide strong evidence that stable, crypt-restricted immunopositivity for MT results from a mutation affecting expression of the metallothionein gene in a colonic stem cell. This model will provide a useful tool to study factors influencing stem cell mutation frequency and cell kinetics in the colon.
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PMID:Crypt-restricted metallothionein immunopositivity in murine colon: validation of a model for studies of somatic stem cell mutation. 1087 53

Dehydroepiandrosterone (DHEA) inhibits glucose 6-phosphate dehydrogenase (G6PD) activity and growth of preneoplastic lesions in various tissues, but its administration may also enhance tumorigenesis by genotoxic carcinogens. We have investigated in single preneoplastic liver lesions, induced in diethylnitrosamine-initiated rats by the resistant hepatocyte protocol, the mechanisms underlying these opposite DHEA effects. Administration of DHEA (0.45% in the diet) for 10 and 26 weeks and of its analog 16alpha-fluoro-5-androsten-17-one (FA, 0.25%) for 10 weeks, starting 4 weeks after initiation, induced an apparent decrease in the number of glutathione S:-transferase (placental) (GST-P)-positive lesions and an increase in lesion volume. DHEA administration for 38 weeks enhanced hepatocellular carcinoma multiplicity. Depending on the rise in the number of slowly growing, remodeling GST-P-positive lesions induced by DHEA and FA, overall DNA synthesis decreased slightly in these lesions at 14 weeks, but increased in uniform lesions. Labeling index (LI) in single uniform lesions at 14 weeks ranged between very low (not different from normal liver) to high (>10-fold normal liver). DHEA and FA induced broad increases in lesions with a high LI, which showed a higher number of cells overexpressing c-Ha-ras and/or c-fos than those with a lower LI. High G6PD activity was inhibited by DHEA and FA in only approximately 50% of preneoplastic lesions. These data indicate selection in rats subjected to long-term DHEA and FA treatments of a subpopulation of GST-P-positive cells with high growth and progression potentials. Overall effects of these compounds depends on the relative numbers of lesions in which inhibition of DNA synthesis can counteract their transforming effect.
Carcinogenesis 2001 Feb
PMID:Long-term dehydroepiandrosterone and 16alpha-fluoro-5-androsten-17-one administration enhances DNA synthesis and induces expression of c-fos and c-Ha-ras in a selected population of preneoplastic lesions in liver of diethylnitrosamine-initiated rats. 1118 52

The pyruvate kinase isoenzyme M2-PK is known to be associated with a metabolic shift that is characteristic for tumor cells. Meanwhile, the universal expression of this isoenzyme is the basis for the detection of various tumor diseases in human clinical diagnosis. Other enzymes which are known to be essential for this tumor specific metabolic shift in rat chemical carcinogenesis are the NADP-dependent enzymes malic enzyme, isocitrate dehydrogenase and glucose 6-phosphate dehydrogenase. To evaluate the role of these enzymes in human carcinogenesis, we compared their enzymatic activities in normal colon mucosa and tissues derived from primary colon tumors. Histochemical staining showed that the enzyme activities were restricted to mucosal colon cells and colon cancer cells. The enzymes were strongly but heterogeneously expressed in the tumor tissues, whereas staining of normal mucosa was weak. Tumor M2-PK showed the most prominent differences in normal colon mucosa and colon cancer cells.
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PMID:Tumor M2-PK and glutaminolytic enzymes in the metabolic shift of tumor cells. 1132 87

Ginkgo biloba extract (EGb) is a natural product that possesses antioxidant and anticlastogenic properties. The current study was conducted to investigate the effect of EGb on benzo(a)pyrene (BP)-induced forestomach neoplasia, and to explore its possible beneficial effects against doxorubicin (Dox)-induced cardiotoxicity. Tumor was induced in female Swiss albino mice by oral administration of 1 mg BP, twice weekly for four weeks. EGb was given, at a daily oral dose of 150 mg kg(-1), two weeks before and during BP administration. Dox was given ip at a dose of 1.5 mg kg(-1), once weekly, for four weeks, during BP administration. EGb and Dox were given as combined or monotherapies. Results of the present investigation revealed that EGb blunted forestomach tumor multiplicity, as compared to control tumor bearing group. It also exhibited high activity to induce cytosolic glutathione S-transferase and glucose-6-phosphate dehydrogenase (G6PDH) in liver, as well as replenished hepatic glutathione that have been inhibited or depleted by tumorigenesis. Furthermore, it normalized nitric oxide (NO) serum level, without any observed alteration in neither the activity of liver microsomal NADPH-cytochrome P-450 reductase nor serum level of tumor necrosis factor-alpha (TNFalpha). Similar results have been obtained with Dox, but it failed to affect G6PDH activity, while increased serum TNFalpha and NO levels. The combined therapy did not add further to the anticarcinogenic effect of Dox, however it succeeded in ameliorating the deleterious effects of Dox on the heart; as evidenced by the reduction of cardiac lipoperoxidation, with modulation of Dox-induced pathological changes. Therefore, EGb confers a beneficial chemopreventive effect against BP-induced gastric carcinogenesis in mice, and possesses a salutary ameliorating potential on the cardiotoxic effects of Dox.
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PMID:Chemopreventive effect of Ginkgo biloba extract against benzo(a)pyrene-induced forestomach carcinogenesis in mice: amelioration of doxorubicin cardiotoxicity. 1137 Aug 28


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