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)

Cachexia and a decreased immune function are negative prognostic factors for cancer patients. While the decreased immunity results in a greater susceptibility to bacterial infection, the response of the host to the resulting infection is not clear. The experiments reported here were designed to evaluate the toxicity of endotoxin to rats with a transplantable Ward colon tumor (WCT) and to evaluate the mechanism of the observed increase in lethal toxicity. The lethal toxicity of endotoxin (lipopolysaccharide, LPS) at 5 mg/kg, i.p. was evaluated in the first of two experiments. Rats received LPS and were observed for morbidity and weight loss for a period of 11 days. A second experiment was done to evaluate the effect of LPS on the plasma nitrate/nitrite concentrations and plasma indicators of host tissue dysfunction. LPS was administered as previously described but blood and tissues were collected 5 h after LPS administration. LPS resulted in the death of 1 of 12 nontumor-bearing (NTB) rats and a transient weight loss in the survivors. This same dose of LPS, however, resulted in death for 10 of 12 WCT rats with tumor burdens less than 4% of body weight. The response of WCT rats 5 h after LPS was then compared with that of age-matched NTB rats. Plasma albumin concentrations were not affected by LPS in NTB rats but were significantly decreased in WCT rats. Peripheral blood gases were not consistently affected by LPS in either group. Peripheral blood white cell counts, except monocytes, were significantly decreased by LPS in both groups. Monocyte counts in peripheral blood were further reduced in WCT rats compared with NTB rats receiving LPS. The presence of the WCT significantly enhanced the LPS-associated increase in spleen weight. Liver weights were lower in LPS rats but there was no effect of the presence of WCT. The LPS-associated increase in plasma nitrate/nitrite concentration was enhanced by the WCT. The plasma arginine and citrulline concentrations were altered in a manner consistent with an increase in nitric oxide synthesis. An increase in plasma ornithine concentration suggests an increase in arginine metabolism by arginase. The plasma concentration of alanine aminotransferase was significantly elevated when WCT rats received LPS, suggesting enhanced hepatic dysfunction. The plasma blood urea nitrogen concentration was elevated by LPS to a greater extent in the WCT rats than in the NTB controls, indicating increased renal dysfunction. These results demonstrate that the Ward colon tumor increases the host lethal response to the endotoxin, a toxic product of bacterial infections. The mechanisms of lethality may include an increased nitric oxide synthesis in WCT rats and enhanced liver and renal toxicity.
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PMID:Influence of the Ward colon tumor on the host response to endotoxin. 917 90

The objective of this study was to elucidate the role and mechanism of nitric oxide (NO) synthase (NOS) in modulating the growth of the Caco-2 human colon carcinoma cell line. The two novel observations reported here are, first, that NG-hydroxy-L-arginine (NOHA) inhibits Caco-2 tumor cell proliferation, likely by inhibiting arginase activity, and, second, that NO causes cytostasis by mechanisms that might involve inhibition of ornithine decarboxylase (ODC) activity. Both arginase and ODC are enzymes involved in the conversion of arginine to polyamines required for cell proliferation. Cell growth was monitored by cell count, cell protein analysis, and DNA synthesis. NOHA (1-30 microM) and NO in the form of DETA/NO (1-30 microM) inhibited cell proliferation by 30-85%. The cytostatic effect of NOHA was prevented by addition of excess ornithine, putrescine, spermidine, or spermine to cell cultures, whereas the cytostatic effect of NO (DETA/NO) and alpha-difluoromethylornithine (ODC inhibitor) was unaffected by ornithine but was prevented by putrescine, spermidine, or spermine. The cytostatic effect of NOHA appeared to be independent of its conversion to NO, and the effect of NO appeared to be independent of cGMP. NOHA inhibited urea production by Caco-2 cells and inhibited arginase catalytic activity (85% at 3 microM), whereas NO (DEA/NO and SNAP) inhibited ODC activity (>/=60% at 30 microM) without affecting arginase activity. Coculture of Caco-2 cells with lipopolysaccharide/cytokine-activated rat aortic endothelial cells markedly slowed Caco-2 cell proliferation, and this was blocked by NOS inhibitors. These observations that NOHA and NO may inhibit sequential steps in the arginine-polyamine pathway suggest a novel biological role for NOS in the inhibition of cell proliferation of certain tumor cells and possibly other cell types.
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PMID:NG-hydroxy-L-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms. 975 58

Alveolar macrophages (AM) were obtained from 20 patients with primary lung cancer and 20 cases with nonmaligment pulmonary disease by BAL and were incubated in vitro in medium with and without BCG and/or IFN-alpha. Then the cell-free supernatants were harvested. The activity of arginase was assayed. It was found that: arginase was produced spontaneously by AM: The spontaneous production of arginase is lower in AMs from the tumor-bearing segments than either nontumor-bearing segments or AMs from the patients with nonmalignant pulmonary diseases (P < 0, .05). The production of arginase was icreased on AMs from the tumor-bearing segments stimulated with BCG and/or IFN-alpha (P < 0.05 or 0.01). The results suggested that (1) There are some function at defects of tumor. (2) The mechanism of anti-tumor and anti-infection activity of BCG and IFN-alpha may possibly increase the production of arginase of AMs.
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PMID:[Study of arginase activity in alveolar macrophages from patients with lung cancer]. 986 39

The physiological significance of arginine metabolism extends far beyond its incorporation as an amino acid into proteins. In addition to its effects when administered as a dietary supplement, the end-products of arginine metabolism by the enzymes arginase, arginine decarboxylase (ADC), and nitric oxide synthase (NOS) have been shown to play roles in wound healing, immune response, tumor biology, and the regulation of inflammation. These properties make arginine metabolism a significant concern in defining and, likely, treating renal disease.
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PMID:Arginine and nutrition in renal disease. 1043 Oct 34

The objective of this study was to elucidate the mechanism by which cyclic AMP increases arginase activity in cultured human Caco-2 tumor cells. Caco-2 cells were incubated for 24 h in the presence of 8-bromo cyclic AMP or forskolin, and the cells were harvested, lysed, and assayed for total arginase activity. Both test agents increased arginase activity by twofold, and this was attributed to the induction of the arginase II isoform. Both arginase II mRNA and protein showed increased expression in response to 8-bromo cyclic AMP and forskolin, and these effects were inhibited by H-89 (protein kinase A inhibitor), enhanced by okadaic acid (phosphatase inhibitor), and enhanced by 1-methyl-3-isobutylxanthine (cyclic nucleotide phosphodiesterase inhibitor). Cyclic GMP did not appear to be involved in arginase II induction. These observations indicate that cyclic AMP stimulates arginase II gene expression by mechanisms involving activation of protein kinase A and consequent activation of appropriate transcription factors.
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PMID:Induction of arginase II in human Caco-2 tumor cells by cyclic AMP. 1066 5

The arginase activity and ornithine level were determined in tissue obtained from patients with non-small cell lung carcinoma (NSLC). The arginase activity and ornithine level in tumor tissues were 1.89 +/- 1.28 U/mg protein and 42.32 +/- 25.82 nmol/mg protein, respectively versus 0.67 +/- 0.19 U/mg protein and 10.12 +/- 3.69 nmol/mg protein for normal tissues (p < 0.01).
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PMID:Arginase and ornithine, as markers in human non-small cell lung carcinoma. 1073 8

l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis. Adult male Wistar rats were treated with azoxymethane (AOM, 15 mg/kg ip), a chemical carcinogen, once a week for 2 weeks. One week after the second injection the rats were randomly divided into two groups. One group (n = 8) received l-NAME (10 mg/kg body wt/day) in drinking water. The control group (n = 8) received tap water. After 5 weeks, the rats receiving l-NAME showed enhanced mean basal arterial blood pressure, decreased heart rate, and a significant decrease of the cGMP content in the colonic mucosa. In both groups, AOM induced the formation of colonic aberrant crypt foci (ACF). In l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis.
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PMID:Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats. 1113 66

Macrophages use L-arginine to synthesize nitric oxide (NO) and polyamines through the inducible NO synthase (iNOS) and arginase, respectively. The released NO contributes to the tumoricidal activity of macrophages, whereas polyamines may promote the growth of tumor cells. Both the tumoricidal and growth-promoting activities from macrophages have been reported; however, the underlying mechanisms for switching between this dual function of macrophages remain unclear. Here, we test the hypothesis that arginase participates in the switching between the cytotoxic and growth-promoting activities of macrophages toward tumor cells. To alter arginase activity in macrophages, cells (murine macrophage cell line J774A.1) were transfected with the rat liver arginase gene or treated with an arginase inhibitor, L-norvaline. The effects of macrophage arginase activity on the growth-promoting and cytotoxic activities of macrophages toward breast tumor cells (ZR-75-1) were investigated in a coculture system. The results demonstrated that overexpression of arginase in macrophages enhanced L-ornithine and putrescine production and consequently promoted tumor cell proliferation. This proliferative effect was down-regulated by the arginase inhibitor L-norvaline. Furthermore, increases in arginase activity also attenuated NO production by the lipopolysaccharide-activated macrophages and thus reduced the cytotoxic effect on cocultured tumor cells. Inhibiting arginase activity by L-norvaline effectively reversed the suppression of NO-mediated tumor cytotoxicity. Together, these results suggest that arginase induction in macrophages can enhance tumor cell growth by providing them with polyamines and suppress tumor cytotoxicity by reducing NO production. It appears that L-arginine metabolism through the arginase and iNOS pathways in macrophages can have very different influences on the growth of nearby tumor cells depending on which pathway is prevailing.
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PMID:Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. 1122 39

During neoplastic development, several aspects of the regulation of polyamine synthesis undergo profound changes. In extrahepatic mammalian tissues in which the urea cycle is not functioning, arginase is believed to supply the cell with ornithine, a non-protein amino acid that is a precursor for biosynthesis of polyamines. Because the activity of ornithine decarboxylase and polyamine levels have been shown to be elevated during carcinogenesis, we decided to investigate the role of arginase in the development of malignant tumors of the human skin and to examine whether arginase activity and ornithine level can be used as biologic markers for distinguishing patients with squamous cell cancer from patients with basal cell cancer. For this purpose, we studied tissue arginase activity and ornithine level in tumor and adjacent normal tissues in 16 patients (55 +/- 10 years of age) with malignant skin tumors (8 of which were squamous cell cancers and 8 of which were basal cell cancers). The mean arginase activity and ornithine levels in tumor tissues (total) were 17.75 +/- 8.54 U/mg protein and 40.89 +/- 14.88 nmol/mg protein, respectively, versus 3.69 +/- 1.71 U/mg protein and 12.98 +/- 6.21 nmol/mg protein, respectively, for normal tissues. The mean specific arginase activity levels in squamous cell and basal cell cancers of the human skin were 18.49 +/- 10.47 U/mg protein and 16.63 +/- 6.00 U/mg protein, respectively. The mean ornithine levels in squamous cell and basal cell cancers of the human skin were 42.45 +/- 19.10 nmol/mg protein and 39.33 +/- 10.19 nmol/mg protein, respectively. Our results indicated that (1) arginase activity and ornithine levels are elevated in squamous cell and basal cell cancers of the human skin; (2) the increased activity of arginase and hence the elevated levels of ornithine may be important in the development of malignant tumors of the human skin; and (3) although arginase activity and ornithine level may be useful for distinguishing patients with malignant skin tumors from healthy subjects, they cannot be used as biologic markers for distinguishing patients with squamous cell cancer from patients with basal cell cancer.
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PMID:Significance of arginase and ornithine in malignant tumors of the human skin. 1132 31

Ornithine decarboxylase is the initial and rate-limiting enzyme in the polyamine biosynthetic pathway. Polyamines are found in all mammalian cells and are required for cell growth. We previously demonstrated that N-hydroxyarginine and nitric oxide inhibit tumor cell proliferation by inhibiting arginase and ornithine decarboxylase, respectively, and, therefore, polyamine synthesis. In addition, we showed that nitric oxide inhibits purified ornithine decarboxylase by S-nitrosylation. Herein we provide evidence for the chemical mechanism by which nitric oxide and S-nitrosothiols react with cysteine residues in ornithine decarboxylase to form an S-nitrosothiol(s) on the protein. The diazeniumdiolate nitric oxide donor agent 1-diethyl-2-hydroxy-2-nitroso-hydrazine acts through an oxygen-dependent mechanism leading to formation of the nitrosating agents N(2)O(3) and/or N(2)O(4). S-Nitrosoglutathione inhibits ornithine decarboxylase by an oxygen-independent mechanism likely by S-transnitrosation. In addition, we provide evidence for the S-nitrosylation of 4 cysteine residues per ornithine decarboxylase monomer including cysteine 360, which is critical for enzyme activity. Finally S-nitrosylated ornithine decarboxylase was isolated from intact cells treated with nitric oxide, suggesting that nitric oxide may regulate ornithine decarboxylase activity by S-nitrosylation in vivo.
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PMID:Nitric oxide inhibits ornithine decarboxylase via S-nitrosylation of cysteine 360 in the active site of the enzyme. 1146 22


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