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)

Staurosporine, which is a potent inhibitor of protein kinases, such as protein kinase C, inhibited both inductions of adhesion of human promyelocytic leukemia cells (50% effective dose = 9.0 nM) and Epstein-Barr virus early antigen in Raji cells (50% effective dose = 3.4 nM) by teleocidin. However, staurosporine induced irritation on mouse ear and histidine decarboxylase activity in mouse skin. It did not induce ornithine decarboxylase activity in mouse epidermis. The two-stage carcinogenesis experiments of staurosporine were carried out at two different doses. Experiment 1 revealed that the group treatment with a single application of 100 micrograms of 7,12-dimethylbenz(a)anthracene, followed by repeated applications of 50 micrograms of staurosporine, resulted in 85.7% of tumor-bearing mice at Wk 30, whereas group treatment with staurosporine alone or 7,12-dimethylbenz(a)anthracene alone gave 6.7% and 0%, respectively. Experiment 2 showed that group treatment with 7,12-dimethylbenz(a)anthracene followed by applications of 10 micrograms of staurosporine resulted in 33% of tumor-bearing mice at Wk 30. In addition, staurosporine treatment reduced the percentages of tumor-bearing mice treated with teleocidin from 100% to 67% in Wk 15. These results demonstrated that staurosporine is a weak tumor promoter of mouse skin compared with teleocidin, but staurosporine has some potency to inhibit tumor promotion by teleocidin.
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PMID:Tumor-promoting activity of staurosporine, a protein kinase inhibitor on mouse skin. 216 51

Okadaic acid (OA) is a potent non-12-O-tetradecanoyl-phorbol-13-acetate (non-TPA) type tumor promoter on mouse skin. OA acts on cells through inhibiting the activity of protein phosphatases and results in the increase of phosphorylation of proteins. Seventeen OA derivatives were evaluated as possible tumor promoters by means of three biochemical tests: inhibition of specific [3H]OA binding to a particulate fraction of mouse skin containing protein phosphatases, inhibition of protein phosphatase activity, and induction of ornithine decarboxylase in mouse skin. Potency in each of these biochemical tests correlated well for each of these derivatives. We present results indicating that the carboxyl group as well as the four hydroxyl groups at C-2, C-7, C-24 and C-27 of OA are important for activity. Acanthifolicin, which gave positive responses in these three biochemical tests as strong as those of OA and dinophysistoxin-1, is predicted to be an additional member of the OA class of tumor promoters.
Carcinogenesis 1990 Oct
PMID:Structure-activity relationship within a series of okadaic acid derivatives. 217 47

The effects of menhaden oil on the choline-deficient (CD) diet tumor promotion regimen-induced alterations in hepatocyte insulin receptors and the cellular ornithine decarboxylase (ODC) activity have been investigated in this study. Male Sprague-Dawley rats exposed to the tumor-promoting regimen of a CD diet for 10 days showed increases in hepatic ODC activity from 2.68 +/- 0.42 pmol 14CO2/mg protein/h in the animals fed basal control chow (C) to 13.54 +/- 2.38 (P less than 0.02) in the rats fed CD diet. These changes in ODC occur simultaneously with the alterations in hormone receptor binding as reported previously for insulin. Replacement of the lipid present in the control diet with 15% menhaden oil (CMO) had no significant effect on ODC activity (0.91 +/- 0.21), or on the number of insulin receptors (206,000 +/- 37,000) and the Kd (7.4 +/- 1.6). Sequential treatment with 10 days of CD diet and then 10 days of the C diet, resulted in a reversal in the elevated, CD-induced hepatic ODC activity to the control levels; however, substituting 15% menhaden oil for the fat present in the CD diet (CDMO) enhanced this enzymatic activity. In contrast, both sequential and CDMO treatments prevented the insulin receptor alterations induced by the CD diet. These data demonstrate that the CD diet-induced insulin receptor alterations occur concurrently with the induction of ODC activity. But insulin receptor changes and the increased ODC activity are affected differently by CDMO treatment, suggesting that their induction by the CD diet is through distinct mechanisms and only the receptor alterations correspond with the tumor-promoting action of CD diet regimen.
Carcinogenesis 1990 Jun
PMID:The effect of menhaden oil on choline-deficiency-induced hepatic ornithine decarboxylase activity and hepatocyte insulin receptor binding. 218 97

Recent evidence has suggested that unsaturated carbonyl compounds may be the ultimate mitogens produced from the primary auto-oxidation products of unsaturated fatty acids. The present study has investigated the metabolism of 13-hydroperoxyoctadecandienoic acid (13-ROOH) by rat colon homogenates. This hydroperoxide is one of the primary products formed from the oxygenation of linoleic acid, the most abundant dietary polyunsaturated fatty acid. Incubation mixtures contained [1-14C]13-ROOH and colonic homogenates prepared from male Sprague-Dawley rats. After 30 min of incubation the reaction was quenched and the products extracted for analysis by HPLC. The identity of the eluted products were verified by UV, MS and NMR spectroscopy. The major products include a mixture of isomers of 2,4-dienone C18 fatty acids and 13-hydroxyoctadecadienoic acid. Direct comparison of homogenate metabolism to the hematin-catalyzed, alkoxyl radical-mediated decomposition of 13-ROOH shows some significant differences. In particular, no epoxy products are detected in the presence of tissue homogenates whereas these are the major products observed during the decomposition of 13-ROOH by hematin and a number of other agents. These experiments demonstrate the production of relatively large amounts of unsaturated carbonyl-containing fatty acids during the metabolism of hydroperoxy fatty acids by colonic tissue. The major product, 13-oxo-9Z,11E-octadecadienoic acid, when instilled intrarectally stimulates the incorporation of [3H]deoxythymidine into colonic mucosal DNA, and induces colonic mucosal ornithine decarboxylase activity in vivo. These findings have important implications for the mechanism by which dietary fat promotes colon tumorigenesis as the formation of relatively reactive 2,4-dienones may be a key to the in vivo mitogenic activity of oxidized fatty acids.
Carcinogenesis 1990 Oct
PMID:Production of unsaturated carbonyl compounds during metabolism of hydroperoxy fatty acids by colonic homogenates. 220 85

The ornithine decarboxylase (ODC) activity and concentration of polyamines have been studied in small and large intestine during 1,2-dimethylhydrazine-induced carcinogenesis in rats. Changes in the polyamine biosynthesis consisting both in enhanced ODC activity and an increase of the intracellular content of putrescine, spermidine and spermine. Process of the polyamine synthesis activation proceeds in two phases: the most expressed and similar changes in polyamine metabolism factors have been observed at early (the 1st month) and late (the 5th-6th months) stages of carcinogenesis. It is supposed that intensification of the polyamine synthesis is a typical feature of malignization in the gastrointestinal tract.
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PMID:[Ornithine decarboxylase activity and polyamine contents in 1,2-dimethylhydrazine-induced carcinogenesis of the intestines in rats]. 226 75

Recent studies of colon adenocarcinomas in humans and experimentally induced colonic tumors in rodents have demonstrated selective elevations in the level of N1-acetylspermidine in these malignant tissues. The exact relationship of these alterations in acetylated polyamine levels to the malignant transformation process, however, remains unclear. In order to clarify this issue, rats were given s.c. injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt/week) or diluent for up to 26 weeks. After 10 weeks of carcinogen treatment, one-half of the animals in each group were also concomitantly given i.p. injections of MDL 72527 (20 mg/kg body wt/week), a specific inhibitor of polyamine oxidase, until they were killed. Animals were killed after 15 weeks of DMH treatment and polyamine levels as well as the activities of polyamine oxidase, ornithine decarboxylase and spermidine-N1-acetyltransferase were measured and compared in rat proximal and distal colonic mucosa of each group. Polyamine levels were also assessed in each of these groups after 26 weeks of treatment with this carcinogen +/- MDL 72527. In addition, in view of recent studies that have indicated that polyamines may influence certain oncogenes in human colonic carcinoma cells, tumors from DMH +/- MDL 72527 were analyzed for K-ras mutations. The results of these experiments demonstrated for the first time that: (i) MDL 72527 was a specific inhibitor of polyamine oxidase in normal and malignant colonic tissue; (ii) concomitant administration of this agent with DMH enhanced the elevation of colonic N1-acetylspermidine and significantly reduced the mean colonic tumor burden, as assessed by total tumor area per rat, produced by this carcinogen alone; (iii) analysis of K-ras mutations revealed a similar incidence (62-69%) in adenocarcinomas for both groups (+/- MDL 72527); (iv) however, analysis of the K-ras-mutated and non-mutated tumors revealed that in both carcinogen-treated groups (+/- MDL 72527), tumors with such mutations were smaller than their counterparts without such genetic alterations. Moreover, MDL 72527 reduced the average size of tumors, with and without such mutations, to a similar extent.
Carcinogenesis 1990 Dec
PMID:Effect of polyamine oxidase inhibition on the colonic malignant transformation process induced by 1,2-dimethylhydrazine. 226 65

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 +/- 23 vs. 120 +/- 23 nmoles.g colon-1, p less than 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 +/- 11 vs. 234 +/- 33 nmoles.g colon-1, p less than 0.01) and in the cecum (59 +/- 13 vs. 121 +/- 33 nmoles.g colon-1, p less than 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 +/- 2.0 vs. 9.1 +/- 1.8 cells.crypt-1.h-1, p less than 0.01), but not cecal (18.9 +/- 1.3 vs. 22.2 +/- 3.3 cells.crypt-1.h-1, p greater than 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 +/- 18 vs. 22 +/- 6 pmoles.hr-1.mg protein-1, p less than 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.
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PMID:Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat. 229 96

Bile acids were been implicated in several pathologic processes, such as secretory diarrhea, carcinogenesis, and immunomodulation of human peripheral blood lymphocytes. Nevertheless, their effect on the human gut immune system is not known. In this study we investigate the effect of several bile acids (cholate, deoxycholate, chenodeoxycholate) and 13-hydroperoxylinoleic acid (conc. 0.1-1000, microM) on human colonic lamina propria lymphocyte (LPL) DNA synthesis and cell proliferation. In addition, the effect of these bile acids on LPL ornithine decarboxylase activity was also determined. Significant dose-dependent inhibition of [3H]thymidine incorporation in Con A-stimulated LPL was observed. Parallel inhibition was seen on LPL cell proliferation. Furthermore, bile acids inhibited ornithine decarboxylase activity in Con A-stimulated LPL. These effects on cell proliferation were not due to the LPL cytolysis as viability and cell membrane integrity were not altered. Our results suggest that bile acid has an immunoregulatory function on the human mucosal immune system and may have a role during pathological states.
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PMID:Modulation of human colonic lamina propria lymphocyte proliferation. Effect of bile acids and oxidized fatty acids. 230 78

UV radiation plays an important role in the induction of cutaneous malignancy, including basal cell and squamous cell carcinomas and malignant melanoma. In addition to its effects on DNA damage and repair mechanisms, UV radiation has been shown to modulate the expression of specific genes, altering the levels of their mRNAs and the synthesis of their corresponding proteins. In order to gain further information about the molecular effects of UV radiation, we have studied the regulation of ornithine decarboxylase (ODC) gene expression in response to UVB radiation. ODC is the rate-limiting enzyme in polyamine biosynthesis, is involved in growth and differentiation, and has been implicated in carcinogenesis. Keratinocytes grown in culture were either sham-irradiated or exposed to increasing doses of UVB (1-5 mJ/cm2). Northern blot analysis of keratinocyte RNA under basal conditions demonstrated the presence of two ODC mRNA transcripts. Increasing exposure to UVB resulted in a dose-dependent increase in the levels of both ODC mRNA transcripts. The induction of ODC gene expression following UVB was noted 2 h after UVB exposure, and ODC mRNA levels continued to increase up to 24 h after UVB exposure. The UVB-induced increase in ODC gene expression was not serum dependent, despite the ability of serum alone to induce ODC gene expression. The mRNA transcripts for actin and hexosaminidase A were not induced after UVB exposure. These studies show that the UVB-induced increase in ODC activity is due, at least in part, to an increase in ODC gene expression and they provide a useful model for the analysis of the molecular effects of UVB radiation.
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PMID:Ultraviolet radiation induction of ornithine decarboxylase in rat keratinocytes. 232 89

The activities of the growth-related enzymes ornithine decarboxylase (ODC) and casein kinase II (CK-II) were assayed along the colon crypt axis in a precise temporal sequence following administration of 1,2-dimethylhydrazine (DMH) to male rats. The time course of events monitored in colonic cell populations sequentially harvested by a scraping procedure shows that the potent carcinogenic insult induces an early and late ODC activity peak: the distinct biphasic response of the decarboxylase was observed in all colonic crypt compartments. The activity gradient of CK-II was markedly altered in DMH-treated cell populations: brisk activity of the kinase was observed in the upper crypt zone, the preserve of the mature, non-dividing colonocyte. The enhanced responses of ODC and of CK-II to DMH proceeded the actual polyp and tumor formation. The polycations spermine and spermidine, bioactive molecules formed in the ODC-controlled polyamine pathway, were shown to markedly activate colonic CK-II. This observation suggests that ODC and CK-II, enzymes with different catalytic purposes, crosstalk within the colonic crypt continuum. The present findings indicate that the differentiation arrest of colonic cells and their misplacement in forbidden zones of the crypt axis during DMH-induced carcinogenesis is accompanied by early alterations in the activity and topology of disparate enzymes which are part of the orderly growth program of the normal colonic cell.
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PMID:Growth-related enzyme activities in crypt compartments during rat colon carcinogenesis. 236 91


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