Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether the activation of inducible nitric oxide synthase (iNOS) can serve as a target for immunotherapeutic agents for treatment of murine reticulum cell sarcoma metastases. Liver metastases were established by the i.v. injection of M5076 cells into syngeneic C57BL/6 mice. Multiple systemic administrations of multilamellar vesicle-liposomes (MLV) containing the lipopeptide CGP 31362 (MLV-31362) or MLV-31362 combined with murine IFN-gamma eradicated the metastases. Tumor regression correlated with iNOS expression within the tumor lesions detected by Northern blot and immunohistochemistry techniques and with increased production of nitric oxide (NO). The administration of a specific iNOS inhibitor, NG-methyl-L-arginine, significantly decreased NO production and diminished the antitumor activities of the immunomodulators. Consistent with the regression of hepatic metastases, the combination of MLV-31362 and IFN-gamma synergistically induced iNOS gene expression, NO production, and apoptosis in the tumor cells under in vitro and in vivo conditions. The addition of NMA prevented the production of NO and apoptosis. These data imply that multiple systemic administrations of MLV-31362 plus IFN-gamma activate endogenous iNOS in sarcoma cells, which then undergo apoptosis, leading in turn to the regression of M5076 sarcoma hepatic metastases.
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PMID:Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362. 754 13

The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly and only a few survive and proliferate to form distant metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Metastatic cells of the murine K-1735 melanoma survive in the circulation to produce experimental lung metastases, whereas nonmetastatic cells do not. After incubation with different cytokines or LPS, nonmetastatic cells exhibit a high level of inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production, whereas metastatic cells do not. To provide direct evidence for the inverse correlation between the production of endogenous NO and the ability of K-1735 cells to produce metastasis in syngeneic mice, highly metastatic clone 4 cells (C4.P), which express low levels of iNOS, were transfected with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM NMA. C4.P, C4.Neo3, and C4.S2.3 cells were highly metastatic, whereas C4.L8.5 cells were not. Moreover, C4.L8.5 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other three cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with apoptosis. Multiple intravenous injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Collectively, these data demonstrate that the expression of iNOS in tumor cells is associated with apoptosis, suppression of tumorigenicity, abrogation of metastasis, and regression of established hepatic metastases.
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PMID:Activation of nitric oxide synthase gene for inhibition of cancer metastasis. 869 Oct 63

Interactions between metastasizing tumor cells and host cells in target organs determine the outcome of metastasis. This review discusses the dual role of activated host endothelial cells in the metastatic process. On one hand, the upregulation of the expression of particular adhesion molecules leads to increased tumor cell binding, and the stimulation of angiogenesis provides the vascular support for the growth of already established metastases. On the other hand, endothelial cells can contribute to host anti-metastatic responses, e.g. by production of the cytotoxic molecule nitric oxide (NO) from arginine with the help of the inducible nitric oxide synthase (iNOS). Using a well-characterized ESbL-lacZ mouse T lymphoma model with a typical three phasic growth profile, we showed during the period of growth retardation a stimulation of NO production by ex vivo isolated liver sinusoidal endothelial cells. The induction of NO synthesis in liver endothelial cells did not require the presence of Kupffer cells and appeared to be stimulated by and dependent on mature T lymphocytes. A breakdown of this NO synthesis coincided with the second tumor expansion phase.
Cancer Metastasis Rev 1996 Jun
PMID:Liver endothelial cells: participation in host response to lymphoma metastasis. 884 99

The process of cancer metastasis consists of multiple sequential and highly selective steps. The vast majority of tumor cells that enter the circulation die rapidly; only a few survive to produce metastases. This survival is not random. Metastases are clonal in origin and are produced by specialized subpopulations of cells that preexist in a heterogeneous primary tumor. Experimental studies concluded that metastatic cells survive in the circulation whereas nonmetastatic cells do not. In part, this difference is due to an inverse correlation between expression of endogenous inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO) and metastatic potential. Direct evidence for the role of iNOS in metastasis has been provided by our data on transfection of highly metastatic murine K-1735 clone 4 (C4.P) cells which express low levels of iNOS, with a functional iNOS (C4.L8), inactive mutated iNOS (C4.S2), or neomycin resistance (C4.Neo) genes in medium containing 3 mM of the specific iNOS inhibitor NG-L-methyl arginine (NMA). C4.P, C4.Neo, and C4.S2 cells were highly metastatic, whereas C4.L8 cells were not. Moreover, C4.L8 cells produced slow-growing subcutaneous tumors in nude mice, whereas the other 3 cell lines produced fast-growing tumors. In vitro studies indicated that the expression of iNOS in C4.L8.5 cells was associated with either cytostasis or cytolysis via apoptosis, depending upon NO output. The tumor cells producing high levels of NO underwent autocytolysis and produced cytolysis of bystander cells under both in vitro and in vivo conditions. Multiple i.v. injections of liposomes containing a synthetic lipopeptide upregulated iNOS expression in murine M5076 reticulum sarcoma cells growing as hepatic metastases. The induction of iNOS was associated with the complete regression of the lesions. Transfection of interferon-beta suppressed tumor formation and eradicated metastases, which was apparently linked to iNOS expression and NO production in host cells such as macrophage. Besides mediating cell death, NO produced tumor suppression by regulating expression of genes related to metastasis, e.g., survival, invasion, and angiogenesis. Suppression of metastasis can be achieved through use of immunomodulators that induce iNOS expression in tumor lesions or by the direct delivery of the iNOS gene to tumor cells or host cells through liposome and/or viral vectors.
Cancer Metastasis Rev 1998 Mar
PMID:Therapy of cancer metastasis by activation of the inducible nitric oxide synthase. 954 23

Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
Cancer Metastasis Rev 1998 Mar
PMID:The role of nitric oxide in interleukin-2 therapy induced hypotension. 954 27

IL-12 is a potent immunoregulatory cytokine that has been shown to mediate tumor regression in a variety of tumor models. We describe the construction of AdCMV-IL-12, a recombinant adenovirus that encodes both subunits of IL-12 under transcriptional control of the CMV promoter. This recombinant virus efficiently infects a wide variety of cell types leading to the production of high levels of biologically active IL-12. Because the liver is a primary site of infection after i.v.-administered adenovirus, we tested the therapeutic efficacy of this virus in a murine hepatic metastasis tumor model. Systemic administration of AdCMV-IL-12 dramatically inhibited the formation of 3-day Renca hepatic metastases (mean of 16 metastases per liver) compared with the control virus AdCMV-betagal (mean of 209) or vehicle alone (mean of 272). Histologic analysis indicated that metastatic growth inhibition was accompanied by a dramatic perivascular infiltrate consisting of T cells, macrophages, and neutrophils. Therapeutic efficacy was not diminished in animals depleted of CD4+ or CD8+ T cells, or in SCID mice, even after NK cell ablation. In the latter case, a hepatic perivascular infiltrate composed of macrophages and neutrophils was observed after AdCMV-IL-12-treatment, while numerous activated Kupffer cells were noted in the hepatic parenchyma. Analysis of therapy-induced changes in hepatic gene expression demonstrated increased levels of IP-10 and Mig RNAs, but no increase in iNOS, Fas, or FasL RNA levels was observed. Our data suggest a model of metastatic growth inhibition mediated by nonlymphocyte effector cells including macrophages and neutrophils and that may involve anti-angiogenic chemokines.
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PMID:T cell- and NK cell-independent inhibition of hepatic metastases by systemic administration of an IL-12-expressing recombinant adenovirus. 960 49

Expression of inducible nitric oxide synthase (iNOS) and its cellular localization was investigated in subcutaneous or lymph node metastases of human melanoma. Immunohistochemistry revealed that iNOS expression was limited to melanoma cells. In samples of patients without distant metastases, the number of iNOS+ tumour cells/total tumour cells was 55% +/- 17% (n = 12) compared with 9% +/- 8% when distant metastases of lung, liver or brain occurred within an observation period of 3 years (n = 10) (P < 0.001). Western blotting confirmed the expression of iNOS protein in select cases. Notably, iNOS is expressed in regional melanoma metastases and its expression is inversely related to the tumour's metastatic potential. Thus, iNOS expression may have predictive value for the development of distant metastases of human melanoma.
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PMID:Inducible nitric oxide synthase (iNOS) expression may predict distant metastasis in human melanoma. 1018 14

An inverse correlation exists between expression of the inducible nitric oxide synthase (iNOS) gene and the ability of cloned K1735 murine melanoma cell lines to metastasize. We have analyzed the basis for the difference in iNOS induction by interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) in metastatic and non-metastatic K1735 cells. Nuclear run-on (NRO) assays revealed an upregulation of iNOS transcription on treatment with IFN-gamma plus LPS in nonmetastatic cells but not in a metastatic line. Transcription factors IFN regulatory factor 1 (IRF-1) and NF-kappaB were induced and functional in both metastatic and nonmetastatic K1735 lines treated with IFN-gamma plus LPS. Furthermore, a reporter construct driven by the wild-type iNOS promoter was transcriptionally activated in both nonmetastatic and metastatic cells. The iNOS-inducible phenotype was dominant in somatic cell hybrids generated by the fusion of nonmetastatic and metastatic cells, suggesting that no inhibitors of iNOS expression are present in metastatic cells. We conclude that the selective block in iNOS transcription in metastatic K1735 cells is likely due to an alteration in iNOS gene regulatory sequences. However, no such alteration was detected within the 1.7 kb iNOS promoter region in metastatic cells.
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PMID:Transcriptional basis for the differences in inducible nitric oxide synthase (iNOS) expression between nonmetastatic and metastatic murine melanoma cell lines. 1033 91

Previously we described that the adoptive transfer of tumor-infiltrating lymphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established methylcholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congenic murine model. The in vivo efficacy of TIL was associated with their ability to secrete interferon-gamma (IFN-gamma), and to a lesser extent granulocyte-macrophage colony-stimulating factor. The local secretion of these cytokines resulted in recruitment of naive host immune cells to the tumor and eventually in a successful host antitumor immune response. In the present study, to further evaluate the role of IFN-gamma in the induction of a host antitumor immune response, we compared the treatment efficacy of adoptively transferred T cells and IFN-gamma gene transfected tumor cells (MCA-105/IFN-gamma) as delivery systems of IFN-gamma. Treatment with TIL-IL-2 or irradiated MCA-105/IFN-gamma induced a similar reduction in pulmonary metastases of MCA-105 tumor. In contrast, irradiated wild-type MCA-105 or TIL from IFN-gamma gene knockout mice did not cause tumor eradication. MCA-105 tumor-bearing mice treated with MCA-205/IFN-gamma showed a partial reduction in the number of pulmonary metastases. Histologically, lungs of successfully treated mice showed that initially activated macrophages expressing inducible nitric oxide synthase (iNOS) and dendritic cells infiltrated the tumor bed. Subsequently, CD4+ and CD8+ T cells infiltrated tumors. The therapeutic efficacy of IFN-gamma transfected tumor cells was eliminated when either CD4+ T cells or CD8+ T cells were depleted. These results suggest that local secretion of IFN-gamma induces a tumor-specific host antitumor immune response mediated through activated macrophages, dendritic cells, and tumor-specific T cells. This may be a common component of successful immunotherapy.
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PMID:Local secretion of IFN-gamma induces an antitumor response: comparison between T cells plus IL-2 and IFN-gamma transfected tumor cells. 1040 33

Newcastle Disease Virus (NDV), an agent with interesting immune stimulatory and anti-tumor activity, was investigated for its capacity to activate anti-tumor activity in murine macrophages in vitro and in vivo. Direct macrophage activation was seen under a variety of experimental conditions using two different strains of NDV, different sources of macrophages (spleen and peritoneum) and different strains of mice (DBA/2, C57BL/6, 615). Various macrophage enzymes (ADA, iNOS, lysozyme, acid phosphatase) became upregulated and anti-tumor effector molecules such as nitric oxide (NO) and TNF-alpha were found in the supernatant. NDV activated macrophages performed anti-tumor activity in vitro such as anti-tumor cytostasis and anti-tumor cytotoxicity. The cytotoxic anti-tumor activity was broad and active against all tumor lines tested including mammary carcinoma, lung carcinoma, mastocytoma and immune escape variants (lymphoma). Macrophage activation via BCG/LPS also caused a broad range anti-tumor cytotoxic activity while activation via mixed lymphocyte culture conditioned medium had restricted anti-tumor activity. Anti-tumor activity of NDV activated macrophages could be transfered in vivo. Transfer of macrophages which had not been appropriately activated exerted either no effect or a tumor growth augmenting effect. Repeated intravenous transfer of NDV activated macrophages exerted a significant suppressive effect on pulmonary metastases in a mammary carcinoma tumor model as well as in a lung carcinoma model. Taken together these results demonstrate that NDV can strongly activate macrophages to perform anti-tumor activities in vitro and in vivo.
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PMID:Newcastle disease virus activates macrophages for anti-tumor activity. 1063 82


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