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)

The activation of the inducible isoform of nitric oxide synthase (NOS) is associated with the production of large quantities of nitric oxide in response to cytokine stimulation. Bacillus Calmette-Guerin (BCG) mode of action against bladder carcinoma remains unclear, although a plethora of local and systemic events may follow its intravesical instillation. The present study was designed to investigate the expression of inducible NOS in normal and neoplastic urothelium and its alteration following tumor resection and subsequent intravesical immunotherapy. Bladder carcinoma and autologous normal bladder tissue specimens were procured from 36 patients undergoing transurethral resection. Tissue specimens were obtained from the same patients at first cystoscopy following six weekly intravesical instillations. Inducible NOS protein expression was assessed by immunohistochemistry in all tissue specimens. Immunostaining of normal urothelium for iNOS before treatment was negative in all but four cases. BCG treatment induced iNOS expression in tumor-free bladder tissue in 24 cases (66.6%). There were only four early tumor recurrences; interestingly, they corresponded to the cases with tumor cells expressing iNOS before BCG treatment, while novel tumors were also iNOS immunoreactive. BCG upregulated iNOS expression in normal human urothelial cells in vivo suggesting a role for nitric oxide in BCG mediated antitumor activity. Inducible NOS was detected in certain tumor specimens before and after BCG treatment implying a possible involvement in pro-tumor action.
Nitric Oxide 2005 Aug
PMID:The effect of intravesical Bacillus Calmette-Guerin instillations on the expression of inducible nitric oxide synthase in humans. 1596 23

The expression of inducible nitric oxide synthase (iNOS) is markedly elevated in rat colon cancers induced by azoxymethane (AOM). In addition, iNOS can be detected in most adenomas and dysplastic aberrant crypt foci (ACF), suggesting that iNOS plays an important role in colon carcinogenesis. In the present study, the effect of an iNOS inhibitor, ONO-1714 ((1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0] heptane hydrochloride), on AOM-induced rat colon carcinogenesis was investigated. Male F344 rats were treated with 15 mg/kg body weight of AOM once a week, for 2 weeks. ONO-1714 was given to the rats at doses of 10, 20, 50, and 100 ppm in diet for 4 weeks from the day before the first carcinogen treatment. The number of AOM-induced ACF in the rats receiving 10, 20, 50 and 100 ppm ONO-1714 were 94, 73 (P < 0.05), 71 (P < 0.005), and 53% (P < 0.0005), respectively, of the control value. Moreover, the mean number of aberrant crypts per focus was significantly lowered in 100 ppm ONO-1714 group (P < 0.05). Then, the effects of long-term treatment (32 weeks) with 50 and 100 ppm ONO-1714 on AOM-induced colorectal tumor development were examined. Although incidences and multiplicities of colon tumors did not significantly differ among the groups, number of tumors developing in the middle part of colon were reduced with both 50 and 100 ppm doses (P < 0.05). Furthermore, colon tumor volume tended to be decreased by ONO-1714 treatment, and the number of colon tumors more than 3mm in diameter was significantly lowered in the 100 ppm ONO-1714 group (P < 0.01). These results suggest that iNOS plays roles in both early and late stages of colon carcinogenesis.
Nitric Oxide 2006 Mar
PMID:Suppressive effect of an inducible nitric oxide inhibitor, ONO-1714, on AOM-induced rat colon carcinogenesis. 1612 53

The cells of a weakly tumorigenic and non-metastatic murine fibrosarcoma (QR-32) are converted into highly malignant tumors (acquiring metastatic potential) once they have grown in vivo after being co-implanted with gelatin sponge which induces inflammation. In the present study, we examined whether nitric oxide (NO) is involved in the inflammation-based tumor progression by administrating a specific inhibitor to inducible nitric oxide synthase, aminoguanidine (AG). First, we co-implanted 1 x 10(5) QR-32 cells with gelatin sponge (10 x 5 x 3 mm piece) into a subcutaneous space in C57BL6 mice. Administration of AG in drinking water (1%) had started 2 days before the tumor implantation and continued until the termination of the experiment. The incidence of tumor formation and the tumor growth did not differ between AG-treated group and -untreated group. On day 28, we excised the arising tumors to establish culture cell lines for evaluation of their acquisition of metastatic phenotype in other normal mice. Metastasis incidence and the number of metastatic colonies were significantly reduced in the tumor cell lines obtained from AG-treated mice compared to those from non-treated mice (p < 0.05). Immunohistochemical analysis demonstrated that inducible nitric oxide synthase and nitrotyrosine in the inflamed lesion were reduced in the AG-administered mice. However, intensity of 8-hydroxy-2-deoxyguanosine was not different between the groups. These results showed that nitric oxide and its reactive nitrogen oxide species cooperatively play a pivotal role in the progression of benign tumor cells in inflamed lesions.
Nitric Oxide 2006 Mar
PMID:Involvement of reactive nitrogen oxides for acquisition of metastatic properties of benign tumors in a model of inflammation-based tumor progression. 1612 21

The purpose of the study was to analyze endogenous nitric oxide (NO) formation and NO-synthase (NOS) gene expression in the urinary bladder from patients with urinary bladder cancer and to investigate the relationship between local NO formation, treatment with Bacillus Calmette Guerin (BCG) and clinical stage in bladder cancer patients. One hundred and three patients with bladder cancer were studied. Endogenous formation of NO was measured in 72 patients, including 6 patients with BCG treated bladder cancer and 6 tumor free control subjects. iNOS expression was analyzed at transcriptional and protein level in biopsies from 31 patients with bladder cancer by real time polymerase chain reaction (PCR) and Western blot (WB), respectively. Three patients in this group had received BCG treatment. Eight biopsies from normal bladder served as control for PCR and WB analysis. Patients with carcinoma in situ (CIS) had higher iNOS expression (p<0.01) and NO formation (p<0.01) than control subjects and patients with papillary tumors without concomitant CIS. Markedly increased iNOS expression (p<0.05) and NO formation (p<0.001) were also found in patients treated with BCG as compared to the other groups. In conclusion, the presence of elevated NO concentration and iNOS expression in the urinary bladder from BCG treated patients and patients with CIS further supports the notion that NO may be an important factor in bladder cancer biology and that the BCG effect on superficial bladder cancer may partly be due to stimulation of local NO formation.
Nitric Oxide 2006 Dec
PMID:Enhanced formation of nitric oxide in bladder carcinoma in situ and in BCG treated bladder cancer. 1651 87

NALM-6 is a pre-B leukemia cell line sensitive to exogenous nitric oxide (NO), which enters into apoptosis during 24 h of exposure to low doses of the NO donors SNAP (100 microM) or DETA-NO (250 microM). By culturing NALM-6 with repeated and increasing concentrations of SNAP, we obtained a variant (NALM-6R) that retains >95% viability and does not enter into apoptosis during 24 h culture in the presence of up to 500 microM SNAP or 750 microM DETA-NO. A power blot screen performed with 277 antibodies on cell lysates from NALM-6 and NALM-6R cultured without NO donors served to determine the altered constitutive expression of 19 proteins in NALM-6R. Proteins affected in the less sensitive cell line NALM6-R are involved in the regulation of apoptosis, the cell cycle, cell interactions, signal transduction, cell morphology, and cell motility. This model shows that repeated exposure of tumor cells to NO may either select NO-resistant cells or contribute to NO-sensitive conversion into NO-resistant cells. The identification of the proteins that are affected during this transition may help us to define the mechanisms that are involved in cell resistance to NO-cytotoxicity which often accompany clinical progression.
Nitric Oxide 2006 Dec
PMID:Altered expression of key cellular gene products accompanies development of resistance to nitric oxide. 1667 76

Tumors produce several factors, such as Prostaglandins (PGs), Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor (TGF)-beta, which may directly or indirectly inhibit the immune response and may hamper immunotherapy. Furthermore, cells of innate or adaptive immunity, recruited by tumor-derived factors, may contribute in immunosuppression. Regulatory T (Treg) cells such as the "naturally occurring" CD4(+)/CD25(+) Treg and the IL-10-induced Tr1 cells are major players in this arena. Paradoxically Treg cells are stimulated by IL-2, which is used in tumor immunotherapy. Treg cells suppress T cell responses through soluble factors or by contact-dependent mechanisms, such as the Cytotoxic T Lymphocyte Antigen (CTLA)-4-mediated induction of Indoleamine 2,3-Dioxygenase (IDO) in dendritic cells (DC). IDO inhibits T cell responses by depleting Tryptophan and producing Kynurenine, which is toxic to lymphocytes. Macrophages, granulocytes or myeloid suppressor cells (MSC) suppress immunity by other enzymatic mechanisms, involving Arginase and Nitric Oxide Synthase (NOS). Subversion of tumor immunosuppression is required for successful immunotherapy. Attempts to block or eliminate Treg cells have been made by the use of chemotherapy, anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40 ligands. Tumor cells genetically modified to secrete IL-21 (an immune-stimulatory "IL-2-like" cytokine, which is not involved in immune regulation) cured experimental metastases in combination with anti-CD25 monoclonal antibodies (mAbs). Also strategies aimed at blocking enzyme-based immune-suppressive mechanisms are suitable, as suggested by experimental evidences in mouse tumor models.
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PMID:Targeting tumor-related immunosuppression for cancer immunotherapy. 1701 74

Spin trapping/electron paramagnetic resonance (EPR) spectroscopy allows specific detection of nitric oxide (NO) generation, in vivo. However, in order to detect an EPR signal in living organism, usually a stimulation of immune system with LPS is used to achieve higher than physiological NO levels. Here, we report non-invasive spin trapping of NO in tumors of non-treated, living animals. EPR spectroscopy was performed at S-band to detect NO in Cloudman S91 melanoma tumors growing in the tail of living, syngeneic hosts-DBA/2 mice. Iron (II) N-(dithiocarboxy)sarcosine Fe2+(DTCS)(2) was used as the spin trap. The results were confirmed by X-band ex vivo study. A characteristic three-line spectrum of NO-Fe(DTCS)(2) (A(N)=13 G) was observed (n=4, out of total n=6) in non-treated tumors and in tumors of animals treated with l-arginine. Substrate availability did not limit the detection of NO by spin trapping. Half-life time of the NO-Fe(DTCS)(2) in tumor tissue was about 60 min. The feasibility of non-invasive spin trapping/EPR spectroscopic detection of NO generated in tumor tissue in living animals, without additional activation of the immune system, was demonstrated for the first time.
Nitric Oxide 2007 Mar
PMID:In vivo spin trapping of nitric oxide from animal tumors. 1711 95

Endothelial nitric oxide synthase (ecNOS) derived nitric oxide (NO) is a key contributor to the angiogenic process. By augmenting angiogenesis NO could potentially promote tumor progression. The object of this study was to determine how knockdown of ecNOS affects endothelial NO production and the angiogenic response in endothelial cells. EOMA cells derived from a spontaneously arising murine hemangioendothelioma were genetically manipulated to stably express siRNA targeting ecNOS. Knockdown of ecNOS in different stably transfected EOMA cell lines was demonstrated by quantitative RT-PCR, Western blot and ecNOS specific ELISA. An EOMA cell line with near complete knockdown of ecNOS exhibited dramatically altered morphology and changes in the expression of mRNAs encoding proteins involved in angiogenesis. This cell line exhibited a 4-fold increase in proliferation in vitro, altered tube formation in matrigel and formed tumors in mice more rapidly than the parental cells. In contrast, a cell line in which ecNOS protein levels were reduced only 5-fold did not show changes in proliferation rate, tube formation or tumor growth. These results suggest that ecNOS derived nitric oxide reduces the growth of hemangioendothelioma derived tumors, and underscore the importance of careful consideration of the tumor type when selecting modulation of nitric oxide signaling as a treatment strategy.
Nitric Oxide 2007 Jun
PMID:Knockdown of endothelial NOS by lentivirus-mediated short hairpin RNA in hemangioendothelioma cells increases proliferation and tumor formation. 1745 14

Interleukin (IL)-1 and tumor necrotic factor alpha (TNFalpha) are pivotal in the pathogenesis of endotoxemia. In spite of the in vitro finding that IL-1beta, but not TNFalpha, can induce iNOS mRNA and NO production as a single stimulus in hepatocytes in primary culture, the involvement of IL-1 in iNOS induction in the liver has been less clear in vivo. To address this, we challenged IL-1alpha/beta double-knockout (IL-1alpha/beta(-/-)) and TNFalpha(-/-) mice with lipopolysaccharide (LPS). As compared with wild-type mice, the increases in the plasma NO level measured as nitrite and nitrate and hepatic iNOS were significantly reduced in IL-1alpha/beta(-/-) and TNFalpha(-/-) mice 8 and 12h after the LPS challenge. In the wild-type mice, iNOS protein was first detected in Kupffer cells around the portal vein 2h after LPS challenge; and then it spread to hepatocytes throughout the intralobular region of the liver by 8h. Although the expression of iNOS protein was detected in Kupffer cells of both IL-1alpha/beta(-/-) and TNFalpha(-/-) mice, its level was moderate in hepatocytes of IL-1alpha/beta(-/-) mice, but negligible in those of TNFalpha(-/-) mice, 8h after LPS challenge. Concomitant with the expression of iNOS protein in the liver, Toll-like receptor 4, the signaling receptor for LPS, was expressed in hepatocytes of wild-type and IL-1alpha/beta(-/-) mice, but not of TNFalpha(-/-) mice. These results demonstrate that the expression of Toll-like receptor 4 is well correlated with that of iNOS protein in hepatocytes in vivo after LPS challenge and that IL-1 is not essential for the induction of iNOS in hepatocytes in vivo.
Nitric Oxide 2007 Jun
PMID:Interleukin-1 is not essential for expression of inducible NOS in hepatocytes induced by lipopolysaccharide in vivo. 1754 42

Human melanoma tumors cells are known to express the enzyme, inducible nitric oxide synthase (iNOS), which is responsible for cytokine induced nitric oxide (NO) production during immune responses. This constitutive expression of iNOS in many patients' tumor cells, as well as its strong association with poor patient survival, have led to the consideration of iNOS as a molecular marker of poor prognosis, as well as a possible target for therapy. The expression of iNOS in patient tumors was found to associate with nitrotyrosine, COX2, pSTAT3, and arginase. Using human melanoma patients' samples as well as cell lines, we have further evidence supporting intracellular NO production by detection of nitrotyrosine and also by use of DAF-2DA staining. Experiments were performed to scavenge the endogenous NO (with c-PTIO) resulting in melanoma cell growth inhibition; this was restored with SIN-1 (NO and O2-donor) providing data to support a functional role of this gas. Our goal is to understand the aberrant biology leading to this curious phenomenon, and to regulate it in favor of patient treatments.
Nitric Oxide 2008 Sep
PMID:Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis. 1847 17


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