Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell loss patterns of five tumors and their histological findings were investigated in WHT/Ht strain mice. The tumors investigated were squamous cell carcinoma H, squamous cell carcinoma NOS, squamous cell carcinoma TAK, rhabdomyosarcoma KAS, and fibrosarcoma YAS. The present study revealed that histological findings of tumor tissues are not necessarily corded structure presented by Thomlinson and Gray. The five were divided into two groups according to their histological findings, i.e. a corded structure (squamous carcinoma H and NOS) and a non-corded structure (squamous cell carcinoma TAK, rhabdomyosarcoma KAS and fibrosarcoma YAS). The cell loss patterns (125I-iododeoxyuridine retention curves) were also divided into two groups which corresponded to the histological structures. Two tumors with the corded structure (squamous cell carcinoma H and NOS) have a cell loss pattern with a constant shoulder portion (a migration time of tumor cells through a tumor cord from capillary to necrotic region). In these tumors, the cell loss occurred in the necrotic regions. In the other tumors with the non-corded structure, cell loss curves have no constant shoulder portion and cell loss might occur throughout the tumor. The origin of hypoxic cells in these two types of histology are presumably different. The diffusion-limited hypoxia, i.e. chronically hypoxic cells, may be the main cause for the tumors with corded structure. On the other hand, hypoxia as a result of temporary cessation of blood flow within the tumor vasculature, i.e. acutely hypoxic cells, may mainly occur in the tumor with non-corded structure.
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PMID:Two different types of cell loss patterns of murine tumors and their corresponding histological findings and possible mechanisms of production of hypoxic cells. 850 92

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.
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PMID:Nitric oxide and angiogenesis. 1124 73

Both enhanced vascular permeability and angiogenesis of tumor sustain rapid growth of tumor involving many vascular mediators and high vascular density. On the contrary, however, they can be utilized for macromolecular drug delivery to tumor. Impaired reticuloendothelial/lymphatic clearance of macromolecules from the tumor, or lack of such clearance, is another unique characteristic of tumor tissue, which results intratumor retention of macromolecular drugs thus delivered (Figure 1). Consequently, enhanced permeability and retention (EPR) effect is the basis for the selective targeting of macromolecular drugs to tumor, and the EPR concept is now utilized for selective delivery of many macromolecular anticancer agents in aqueous formation for i.v. or i.a. as well as oily formation for i.a. dosing, which is not possible for low-molecular-weight drugs because of rapid washout by capillary vascular blood flow. This EPR concept has been validated in clinical settings with hepatoma and other solid tumors. In our laboratories, several promising macromolecular anticancer drugs after SMANCS, such as PEG-XO, PEG-DAO, PEG-ZnPP, were developed, warranting further investigation for clinical application. More efficient drug delivery to tumor, especially of macromolecular drugs, may be possible by enhancing the EPR effect with the use of various vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors or antidotes, such as the bradykinin antagonist HOE 140 and protease inhibitors or NOS inhibitors, may also be possible. Thus, one may be able to suppress or retard tumor growth and tumor metastasis. Also, by suppressing vascular permeability with antidotes such as the bradykinin antagonist HOE 140, pleural fluid in lung cancer and ascitic fluid in abdominal carcinomatosis may be controlled and the clinical course of cancer patients may be improved. In summary, tumor vasculature can be an excellent target for delivery of macromolecular anticancer drugs; the most beneficial class of drugs in view of tumor-selective targeting based on the EPR effect in solid tumor as well as compliance of patients and ultimate therapeutic efficacy.
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PMID:Factors and mechanism of "EPR" effect and the enhanced antitumor effects of macromolecular drugs including SMANCS. 1267 6

Although vascular endothelial growth factor-165 (VEGF(165)) regulates numerous angiogenic cellular activities, its complex effects on vascular morphology are not highly quantified. By fractal-based, multiparametric branching analysis of 2D vascular pattern in the quail chorioallantoic membrane (CAM), we report that vessel density increased maximally at lower VEGF concentrations, but that vessel diameter and activity of endothelial nitric oxide synthase (eNOS) increased maximally at higher VEGF concentrations. Following exogenous application of human VEGF(165) to the CAM at embryonic day 7, vessel density and diameter were measured after 24 h at arterial end points by the fractal dimension (D(f)) and generational branching parameters for vessel area density (A(v)), vessel length density (L(v)) and vessel diameter (D(v)) using the computer code VESGEN. The VEGF-dependent phenotypic switch from normal vessels displaying increased vessel density to abnormal, dilated vessels typical of tumor vasculature and other pathologies resulted from an approximate threefold increase in VEGF concentration (1.25 to 5 microg/CAM) and correlated positively with increased eNOS activity. Relative to control specimens, eNOS activity increased maximally to 60% following VEGF treatment at 5 microg/CAM, compared to 10% at 1.25 microg/CAM, and was accompanied by no significant change in activity of inducible NOS. In summary, VEGF(165) induced a phenotypic switch from increased vessel density associated with low VEGF concentration, to increased vessel diameter and increased eNOS activity at high VEGF concentration.
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PMID:A VEGF165-induced phenotypic switch from increased vessel density to increased vessel diameter and increased endothelial NOS activity. 1687 39

Heterogeneities in tumor blood flow are associated with cyclic changes in pO2 or cyclic hypoxia. A major difference from O2 diffusion-limited or chronic hypoxia is that the tumor vasculature itself may be directly influenced by the fluctuating hypoxic environment, and the reoxygenation phases complicate the usual hypoxia-induced phenotypic pattern. Here, we determined the cyclic hypoxia-driven pathways that modulate hypoxia inducible factor (HIF)-1alpha abundance in endothelial cells to identify possible therapeutic targets. We found that exposure of endothelial cells to cycles of hypoxia/reoxygenation led to accumulation of HIF-1alpha during the hypoxic periods and the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK) and endothelial nitric oxide synthase (eNOS) during the reoxygenation phases. We identified stimulation of mitochondrial respiration and activation of the phosphoinositide-3 kinase (PI3K)/Akt pathway during intervening reoxygenation periods as major triggers of the stabilization of HIF-1alpha. We also found that the NOS inhibitor nitro-l-arginine methyl ester further stimulated the cyclic hypoxia-driven HIF-1alpha accumulation and the associated gain in endothelial cell survival, thereby mirroring the effects of a PI3K/Akt inhibitor. However, combination of both drugs resulted in a net reduction in HIF-1alpha and a dramatic in decrease in endothelial cell survival. In conclusion, this study identified cyclic hypoxia, as reported in many tumor types, as a unique biological challenge for endothelial cells that promotes their survival in a HIF-1alpha-dependent manner through phenotypic alterations occurring during the reoxygenation periods. These observations also indicate the potential of combining Akt-targeting drugs with anti-angiogenic drugs, in particular those interfering with the NO pathway.
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PMID:Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells--new insights for anti-tumor treatments. 1907 64

Photodynamic therapy (PDT) employs a photosensitizing agent, molecular oxygen, and visible light to generate reactive species that kill tumor and tumor vasculature cells. Nitric oxide produced by these cells could be procarcinogenic by inhibiting apoptosis or promoting angiogenesis and tumor growth. The purpose of this study was to determine whether tumor cells upregulate NO as a cytoprotective measure during PDT. Breast tumor COH-BR1 cells sensitized in their mitochondria with 5-aminolevulinic acid (ALA)-derived protoporphyrin IX died apoptotically after irradiation, ALA- and light-only controls showing no effect. Western analysis revealed that inducible nitric oxide synthase (iNOS) was upregulated >3-fold within 4 h after ALA/light treatment, whereas other NOS isoforms were unaffected. Exposing cells to a NOS inhibitor (L-NAME or 1400W) during photochallenge enhanced caspase-3/7 activation and apoptotic killing up to 2- to 3-fold while substantially reducing chemiluminescence-assessed NO production, suggesting that this NO was cytoprotective. Consistently, the NO scavenger cPTIO enhanced ALA/light-induced caspase-3/7 activation and apoptotic kill by >2.5-fold. Of added significance, cells could be rescued from 1400W-exacerbated apoptosis by an exogenous NO donor, spermine-NONOate. This is the first reported evidence for increased tumor cell resistance due to iNOS upregulation in a PDT model. Our findings indicate that stress-elicited NO in PDT-treated tumors could compromise therapeutic efficacy and suggest NOS-based pharmacologic interventions for preventing this.
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PMID:Cytoprotective induction of nitric oxide synthase in a cellular model of 5-aminolevulinic acid-based photodynamic therapy. 2013 43

Benign prostate hypertrophy (BPH) and prostate cancer (PC) are prostate chronic diseases that require a long period for development from a small lesion to clinical manifestation. PC is the most common cancer in men in Europe and the Americas. Tumor growth and metastasis depend upon the development of neovasculature around the tumor. This process, called angiogenesis, may be regulated by NO, and thus modulation of NO production could play an important role in tumor progression. Recent studies report the involvement of DDAH, an enzyme which metabolizes the endogenous NOS inhibitor ADMA, in the development of tumor vasculature. The aim of the present study was to verify the involvement of the DDAH/NOS pathway in the progression of prostate cancer. The effect of the NOS inhibitor L-NAME was evaluated in the human prostate cancer cell line LnCap and in BPH-1 cells which represent benign prostatic hypertrophy. Higher DDAH-2, eNOS, iNOS and VEGF expression was found in LnCap cells compared to BPH-1 cells. L-NAME treatment of LnCap cells resulted in a reduction in VEGF, iNOS and eNOS expression. VEGF, iNOS and eNOS inhibition is a promising approach for targeting tumor vasculature and certain NOS inhibitors could potentially serve as experimental agents for treatment of certain chemoresistant tumors, including prostate tumors. Moreover, since in our experimental conditions L-NAME was unable to reduce DDAH activity and expression, it is plausible to hypothesize the development of a targeted polypharmacological approach by developing dual and specific inhibitors of DDAH and NOS to better control NO biosynthesis.
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PMID:The DDAH/NOS pathway in human prostatic cancer cell lines: antiangiogenic effect of L-NAME. 2172 Jul 12

Glioma-initiating cells (GIC), which reside within the perivascular microenvironment to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling crosstalk between GICs and endothelial cells are poorly understood. Here, we report that, in both GICs and endothelial cells, platelet-derived growth factor (PDGF)-driven activation of nitric oxide (NO) synthase increases NO-dependent inhibitor of differentiation 4 (ID4) expression, which in turn promotes JAGGED1-NOTCH activity through suppression of miR129 that specifically represses JAGGED1 suppression. This signaling axis promotes tumor progression along with increased GIC self-renewal and growth of tumor vasculature in the xenograft tumors, which is dramatically suppressed by NOTCH inhibitor. ID4 levels correlate positively with NOS2 (NO synthase-2), HES1, and HEY1 and negatively with miR129 in primary GICs. Thus, targeting the PDGF-NOS-ID4-miR129 axis and NOTCH activity in the perivascular microenvironment might serve as an efficacious therapeutic modality for glioblastoma.
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PMID:Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression. 2496 27

Previously, we demonstrated that nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors, and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function-enhancing chemotherapeutic delivery and response to radiotherapy. MMTV-neu mice with spontaneous breast tumors were treated with SP by oral gavage and evaluated by multispectral optoacoustic tomographic analysis of tumor HbO₂ and by tissue staining for markers of hypoxia, blood perfusion, and markers of endothelial and smooth muscle proteins. Recoupling tumor NOS activity results in vascular normalization observed as reduced tumor hypoxia, improved tumor percentage of HbO₂ and perfusion, as well as increased pericyte coverage of tumor blood vessels. The normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone. High-performance liquid chromatography analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.
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PMID:Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization. 2958 Nov 54

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