Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DMXAA (5,6-dimethylxanthenone-4-acetic acid) is an antivascular agent that exerts its antitumor effect at least partly through the induction of tumor necrosis factor (TNF)-alpha. Photodynamic therapy (PDT), the activation of a photoreactive drug in tumor tissue with visible light, is used clinically to control solid malignancies. PDT has been shown previously to be potentiated, in mice, by the i.p. administration of recombinant human TNF-alpha. Here, we investigated the activity of DMXAA as a modifier of Photofrin-based PDT of implanted murine RIF-1 tumors. The DMXAA dose (20 mg.kg(-1)) used throughout this study had little effect on tumor growth. The combination of DMXAA and PDT led to a reduction in tumor volume and significant delays in regrowth, giving a PDT-dose modification factor of 2.81. This enhancement was found to be strongly schedule dependent. The most pronounced responses were achieved when DMXAA was administered 1-3 h before the local illumination of the tumors; less activity was observed at other intervals within +/-24 h of PDT-light delivery. Using a 2-h DMXAA-light interval, histological examination showed significantly reduced blood vessel counts (CD31 immunostaining) and marked necrosis (H&E) in the tumors given combination therapy compared with the tumors given either agent alone. Conversely, peritumoral tissue was still intact 24 h after the combined therapy. DMXAA did not augment the damage to normal mouse feet after low-dose PDT (1.5 mg.kg(-1) Photofrin); however, there was some enhancement of normal tissue phototoxicity when DMXAA was combined with high-dose PDT. The antitumor effect after DMXAA plus low-dose PDT (1.5 mg.kg(-1) Photofrin) appeared to be dependent on TNF-alpha because neutralizing antibodies to this cytokine reduced the tumor response to control levels. DMXAA by itself induced TNF-alpha in RIF-1 tumors whereas PDT did not. However, the addition of PDT after DMXAA resulted in decreases in TNF-alpha, suggesting that the enhanced antitumor activity of the combination therapy was not attributable simply to an increased induction of the cytokine by PDT over that from DMXAA alone. These observations suggest a promising new combination therapy with considerable therapeutic advantage.
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PMID:Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors. 1463 71

Recent studies have evaluated the cytokine network involved in the local immune response to tumors. In addition to infiltrating inflammatory cells, tumors also produce cytokines and growth factors that may alter tumor growth and tumor immunogenicity. Ninety-one samples of NSCLC were used in this study. We measured the expression of VEGF, TNF-alpha, TGF-beta, IL-6, IL-8, IL-12, INF-gamma, and MCP-1 in NSCLC tissues, by ELISA. The expression of IL-6 and IL-8 were significantly higher in squamous cell carcinoma than in adenocarcinoma (p=0.016 and p<0.001, respectively). The expression of TGF-beta, MCP-1 and IL-8 were significantly higher in pulmonary metastasis positive than negative cases (p=0.002, p=0.001, and p=0.008, respectively). In multivariate logistic regression analysis, the expression of TGF-beta was an independent risk factor for the occurrence of pulmonary metastasis (p=0.008, 95% CI=1.002-1.011). We confirmed that tumor infiltrating stromal cells were major sources of TGF-beta by immunohistochemical analysis. The expression of VEGF and IL-8 were significantly higher in cases with central necrosis (p=0.006 and p=0.011, respectively). We speculated that TGF-beta expression in tumor infiltrating stromal cells may regulate the occurrence of spontaneous pulmonary metastasis in NSCLC. (Ann Thorac Cardiovasc Surg 2003; 9: 295-300)
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PMID:Significance of expression of TGF-beta in pulmonary metastasis in non-small cell lung cancer tissues. 1467 25

Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene. In most cases the second wild-type allele is lost in tumor tissue, suggesting that CYLD functions as tumor suppressor. CYLD is a protein of 956 amino acids harboring a functional deubiquitinating domain at the COOH-terminal end. To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD. Mapping of the interacting domains revealed that the central domain of CYLD binds to the COOH-terminal end of TRIP. Far Western analysis and coimmunoprecipitations in mammalian cells confirmed that full-length CYLD binds to the COOH-terminal domain of TRIP. Because TRIP is an inhibitor of nuclear factor (NF)-kappaB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-kappaB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-kappaB activation by TNF-alpha. The inhibition by CYLD depends on the presence of the central domain interacting with TRIP and its deubiquitinating activity. These findings indicate that cylindromas arise through constitutive NF-kappaB activation leading to hyperproliferation and tumor growth.
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PMID:The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. 1467 4

Cytolytic CD8(+) effector cells fall into two subpopulations based on cytokine secretion. Type 1 CD8(+) T cells (Tc1) secrete IFN-gamma, whereas type 2 CD8(+) T cells (Tc2) secrete interleukin (IL)-4 and IL-5. Although both effector cell subpopulations display Fas ligand (FasL) and tumor necrosis factor (TNF), tumor lysis is predominantly perforin dependent in vitro. Using an ovalbumin-transfected B16 lung metastasis model, we show that heightened numbers of adoptively transferred ovalbumin-specific Tc1 and Tc2 cells accumulated at the tumor site by day 2 after therapy and induced tumor regression that enhanced survival in mice with pulmonary metastases. Transfer of either TNF-alpha- or perforin-deficient Tc1 or Tc2 effector cells generated from specified gene-deficient mice showed no differences in therapeutic efficiency when compared with corresponding wild-type cells. In contrast, both Tc1 and Tc2 cells, derived from either FasL or TNF-alpha/lymphotoxin (LT) alpha double knockout mice, showed that therapeutic effects were dependent, in part, on effector cell-derived FasL or LTalpha. Six days after effector cell therapy, elevated levels of activated endogenous CD8/CD44(High) and CD4/CD44(High) T cells localized and persisted at sites of tumor growth, whereas donor cell numbers concomitantly decreased. Both Tc1 and Tc2 effector cell subpopulations induced endogenous antitumor responses that were dependent, in part, on recipient-derived IFN-gamma and TNF-alpha. However, neither effector cell-mediated therapy was dependent on recipient-derived perforin, IL-4, IL-5, or nitric oxide. Collectively, tumor antigen-specific Tc1 and Tc2 effector cell-mediated therapy is initially dependent, in part, on effector cell-derived FasL or LTalpha that may subsequently potentiate endogenous recipient-derived type 1 antitumor responses dependent on TNF-alpha and IFN-gamma.
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PMID:Effector cell-derived lymphotoxin alpha and Fas ligand, but not perforin, promote Tc1 and Tc2 effector cell-mediated tumor therapy in established pulmonary metastases. 1472 52

Edible berry anthocyanins possess a broad spectrum of therapeutic and anti-carcinogenic properties. Berries are rich in anthocyanins, compounds that provide pigmentation to fruits and serve as natural antioxidants. Anthocyanins repair and protect genomic DNA integrity. Earlier studies have shown that berry anthocyanins are beneficial in reducing age-associated oxidative stress, as well as in improving neuronal and cognitive brain function. Six berry extracts (wild blueberry, bilberry, cranberry, elderberry, raspberry seeds, and strawberry) were studied for antioxidant efficacy, cytotoxic potential, cellular uptake, and anti-angiogenic (the ability to reduce unwanted growth of blood vessels, which can lead to varicose veins and tumor formation) properties. We evaluated various combinations of edible berry extracts and developed a synergistic formula, OptiBerry IH141, which exhibited high ORAC (Oxygen-Radical Absorbing Capacity) value, low cytotoxicity, and superior anti-angiogenic properties compared to the other combinations tested. Anti-angiogenic approaches to treat cancer represent a priority area in vascular tumor biology. OptiBerry significantly inhibited both H2O2- and TNF-alpha-induced VEGF (Vascular Endothelial Growth Factor) expression by human keratinocytes. VEGF is a key regulator of tumor angiogenesis. Matrigel assay using human microvascular endothelial cells showed that OptiBerry impaired angiogenesis. In an in vivo model of angiogenesis, OptiBerry significantly inhibited basal MCP-1 and inducible NF-kappaB transcriptions. Endothelioma cells pretreated with OptiBerry showed a diminished ability to form hemangioma and markedly decreased tumor growth by more than 50%. In essence, these studies highlight the novel anti-angiogenic, antioxidant, and anti-carcinogenic potential of a novel anthocyanin-rich berry extract formula, OptiBerry.
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PMID:Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. 1497 22

Transcription factor NF-kappaB plays a pivotal role in cancer cells in the resistance to apoptosis, since NF-kappaB is frequently activated in many primary carcinoma cells. Indeed, several NF-kappaB inhibitors are found to be promising anti-cancer agents. However, some anti-cancer agents activate NF-kappaB signals and may reduce their potential, including tumor necrosis factor (TNF)-alpha. Recently, the nonsteroidal anti-inflammatory drug (NSAID) sulindac and its metabolites have been shown to inhibit the NF-kappaB-mediated survival signals through inhibition of IKK-beta by their direct interaction. We thus investigate whether sulindac and its metabolite can augment TNF-alpha-mediated apoptosis in human carcinoma cells and be applicable for in vivo clinical usage. We here demonstrate that sulindac inhibited TNF-alpha-mediated NF-kappaB activation and greatly enhanced TNF-alpha-induced apoptosis in human gastric MKN45 and cervical HeLa carcinoma cell lines. The in vivo tumor growth of MKN45 cells was most strongly inhibited by a combination of TNF-alpha with sulindac compared with TNF-alpha or sulindac alone. Moreover, we demonstrate that sulindac sulfide further augmented TNF-alpha-mediated apoptosis. Our data strongly suggest that combination therapy of TNF-alpha with sulindac and its metabolites may sensitize cancer cells to TNF-alpha and augment its pro-apoptotic potential. Therefore, in combination with sulindac or its metabolites, TNF-alpha may become a potentially useful anti-cancer agent to suppress tumor.
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PMID:Combination of tumor necrosis factor-alpha with sulindac in human carcinoma cells in vivo. 1503 33

Osteopontin (OPN) expression in tumors is associated with more aggressive tumor growth; however, several studies have suggested that OPN as a host protein can regulate tumor growth as well. OPN is produced by macrophages and T cells, and reportedly modifies macrophage function. Here, we have investigated the effect of OPN on macrophage function, and its role in host defense against tumor growth. OPN deficient (-/-) and wild-type (WT) peritoneal macrophages were assessed for their ability to mediate cytotoxicity of tumor cells. Thioglycollate-elicited peritoneal exudate cells (PEC) were stimulated in vitro with interferon-gamma and lipopolysaccharide. [(3)H]Thymidine-labeled ras-transformed tumor cells were then added and (3)H release and nitrite accumulation were measured. OPN -/- PEC exhibited as much as a 70% reduction in cytotoxicity as compared to WT PEC. Tumor cell OPN status, on the other hand, had little effect on the extent of cytotoxicity. Production of nitrite by the PEC correlated with their capacity to kill tumor cells. L-929 cells, which are relatively resistant to nitric oxide-induced cytotoxicity and sensitive to that effected by TNF-alpha, were killed equally well by wild-type and OPN-deficient PEC, suggesting that the effect of OPN is not mediated through TNF-alpha. No difference was seen in the cytotoxicity of resident macrophages from mice of different genotypes, indicating that the defect in the OPN-deficient macrophages may result from altered differentiation in vivo. In support of this idea, we show that the expression of the macrophage markers F4/80 in peritoneal cells and of Mac-2 in spleen cells is altered in OPN -/- mice as compared to WT. These data support the hypothesis that host-derived osteopontin may inhibit tumor growth and provide a mechanism for this effect.
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PMID:Impaired anti-tumor cytotoxicity of macrophages from osteopontin-deficient mice. 1505 10

Fas ligand (FasL) has been well characterized as a death factor. However, recent studies revealed that ectopic expression of FasL induces inflammation associated with massive neutrophil infiltration. We previously demonstrated that the neutrophil infiltration-inducing activity of FasL is partly dependent on, but partly independent of, IL-1beta. Here we investigated the cytokine profile of peritoneal lavage fluid obtained from mice that received i.p. injections of FFL, a FasL-expressing tumor cell line. We found that FFL injection caused a marked increase of not only IL-1beta but also IL-6, IL-17, IL-18, KC/chemokine CXC ligand 1 and macrophage inflammatory protein (MIP)-2, but not of IL-1alpha, IFN-gamma, TGF-beta or TNF-alpha. The FFL-induced cytokine production was not observed in Fas-deficient lpr mice. Among cells transfected to express individually IL-1beta, IL-6, IL-17, or IL-18, only those expressing IL-1beta and IL-17 induced neutrophil infiltration. In these analyses, as little as 20 pg of peritoneal IL-17 induced neutrophil infiltration. The peritoneal IL-17 levels after FFL-injection were greatly diminished in IL-1-deficient mice. However, the IL-17 level was still above the threshold for neutrophil infiltration. Consistent with this, co-administration of the anti-IL-17 antibody with FFL diminished the peritoneal KC levels and neutrophil infiltration in IL-1-deficient mice. In addition, the expression of IL-17 by the tumor cells inhibited tumor growth in wild-type and nude mice. These results indicate that FasL is an upstream inflammatory factor that induces a variety of other inflammatory cytokines in vivo, and suggest that IL-17 is involved in FasL-induced inflammation in the absence of IL-1beta.
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PMID:Involvement of IL-17 in Fas ligand-induced inflammation. 1523 5

We have previously suggested that thymosin alpha(1) (thyalpha1), an immunomodulating thymic hormone, can activate tumor-associated macrophages to a tumoricidal state in a murine model bearing a transplantable T-cell lymphoma of spontaneous origin designated as Dalton's lymphoma (DL). Since tumor-infiltrating dendritic cells (DC) also play an important role in the host's antitumor response and are as such in an immunocompromised state in a tumor-bearing host, in the present investigation we studied if thyalpha1 is able to influence the differentiation of tumor-associated macrophages (TAM) into DC with granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor (TNF) and whether these TAM-derived DC show enhanced antitumor activity. It was observed that DC generated from thyalpha1-administered tumor-bearing mice showed augmented antitumor activity in vitro. Adoptive immunotherapy using TAM-derived DC showed a significant delay in the tumor growth and a prolongation of the survival time in tumor-bearing mice. DC obtained from TAM of thyalpha1-administered mice also produced an enhanced amount of cytokines like IL-1 and TNF-alpha. This is the first study of its kind regarding the effect of thyalpha1 on the differentiation of DC from TAM and the role of TAM-derived DC in tumor progression.
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PMID:Effect of thymosin alpha 1 on the antitumor activity of tumor-associated macrophage-derived dendritic cells. 1531 38

Upon contact with tumor cells when cocultured in vitro, human monocytes become unresponsive (deactivated) to restimulation and demonstrate decreased production of TNF-alpha and IL-12, and enhanced IL-10 secretion. The present study was undertaken to determine whether immunomodulatory agents (proinflammatory cytokines and PPD of tuberculin) could either prevent or reverse the deactivation of monocytes. Monocytes were treated with the agents either before or after being cocultured with tumor cells. Pretreatment of monocytes with IFN-gamma, either alone or in combination with TNF-alpha, GM-CSF, or PPD, significantly enhanced TNF-alpha and IL-12 production by deactivated monocytes. TNF-alpha, GM-CSF, and PPD alone were inactive. Treatment of monocytes following coculture with IFN-gamma, TNF-alpha, GM-CSF, PPD or IFN-gamma in combination with these agents reversed the depressed TNF-alpha release, whereas IL-12 production was enhanced by IFN-gamma alone. All the agents had no or only a limited effect on the enhanced IL-10 secretion by deactivated monocytes. However, treatment of cocultured monocytes with anti-IL-10 mAb significantly increased the production of TNF-alpha and IL-12 by deactivated monocytes. Moreover, coengraftment of deactivated monocytes with human pancreatic carcinoma cells into SCID mice caused an enhancement of the tumor growth that was alleviated by the treatment of monocytes in vitro with IFN-gamma alone or in combination with GM-CSF or PPD. These results suggest that activation of monocytes with certain proinflammatory cytokines and/or selective inhibition of IL-10 by a mAb may prevent or reverse monocyte deactivation caused by tumor cells.
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PMID:Prevention and reversal of tumor cell-induced monocyte deactivation by cytokines, purified protein derivative (PPD), and anti-IL-10 antibody. 1532 79


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