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)

Several different mouse and rat tumors were injected s.c. or i.v. into specific-pathogen-free young (3-week-old) and adult (6-week-old) nude mice. All tumors grew s.c.; however, following i.v. injections, only metastatic neoplasms produced visible pulmonary tumor foci in the 3-week-old (but not in the 6-week-old) nude mice. The quantitative differences in metastatic potential among tumor lines and clones observed in syngeneic hosts were maintained also when 3-week-old nude mice were used. The enhanced survival of tumor cells in the lungs and the large numbers of visible pulmonary metastases observed in the young nude recipients correlated closely with the low levels of natural killer cell activity detected in 3-week-old (but not in 6-week-old) nude mice. In vivo activation of natural killer cells by treatment of mice with polyinosinic-polycytidylic acid or Corynebacterium parvum, 24 hr prior to tumor challenge rendered th 3-week-old nude mice resistant to development of metastases. We conclude that specific-pathogen-free 3-week-old nude mice, which lack functional T-lymphocytes and demonstrate low natural killer cell activity, could serve as an in vivo model to ascertain the metastatic potential of allogeneic and xenogeneic tumors.
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PMID:Expression of metastatic potential of allogenic and xenogeneic neoplasms in young nude mice. 744 88

The antitumor efficacy of recombinant murine interleukin-1 alpha (rMuIL-1 alpha) was evaluated either alone or in combination with recombinant human hybrid interferon alpha A/D (IFN-alpha A/D) against the murine B16 F10 malignant melanoma. Treatment of subcutaneous tumor-bearing mice intraperitoneally with rMuIL-1 alpha resulted in a dose-dependent inhibition of tumor growth with the greatest activity obtained with the maximum tolerated dose of rMuIL-1 alpha (10 micrograms per treatment). Augmented tumor inhibition comparable to that seen in mice treated with a high dose of rMuIL-1 alpha was observed in subcutaneous tumor-bearing mice injected with the combination of IFN-alpha A/D and a low dose of rMuIL-1 alpha. Similar inhibition of subcutaneous tumor growth was obtained in T-cell-deficient nude or natural killer cell-deficient beige mice. In contrast, treatment of mice bearing B16F10 experimental pulmonary metastases with rMuIL-1 alpha resulted in no decrease in the number of metastases, and rMuIL-1 alpha did not potentiate the antimetastatic activity of IFN-alpha A/D. A synergistic induction of IL-6 was induced in mice treated with the combination of rMuIL-1 alpha plus IFN-alpha A/D but the level of IL-6 induced was not correlated with inhibition of tumor growth because this elevation of IL-6 was not observed in tumor-bearing nude mice. No direct antiproliferative activity was demonstrable in vitro against B16 F10 cells with rMuIL-1 alpha, IL-6, or rMuIL-1 alpha plus IL-6, and addition of these cytokines did not enhance the antiproliferative activity of IFN-alpha A/D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced antitumor efficacy in mice by combination treatment with interleukin-1 alpha and interferon-alpha. 806 95

Despite undergoing a curative resection, many patients with colorectal cancer will develop and die of metastatic disease. It has been shown clinically and experimentally that surgery causes a transient period of immunosuppression, and it is postulated that this may encourage both the implantation of surgically disseminated tumor cells and the growth of existing micrometastases. The present study used natural killer cell cytotoxicity (NKCC) and tumor burden to evaluate perioperative modulation of immunocompetence in a murine model. We measured NKCC and tumor burden responses to a standardized surgical stress (SSS) alone, and to either morphine sulfate (MS) (15 mg/kg subcutaneously x 4 doses), ketorolac (a prostaglandin synthetase--prostaglandin E2--inhibitor) (2.5 mg/kg subcutaneously x 4 doses), or interleukin 2 (2,000 units intraperitoneally x 3 doses) administration with the SSS. In this model, we found that both low-dose interleukin-2 (IL-2) and ketorolac reversed the NKCC suppression associated with surgery, whereas morphine resulted in further depression of NKCC. In addition, IL-2 significantly decreased tumor incidence, whereas continuous MS exposure markedly increased tumor burden after surgery. These data suggest that IL-2 and ketorolac may be effective agents for the restoration of perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects.
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PMID:Perioperative immunomodulation in cancer surgery. 831 Nov 30

We studied the relationship of natural killer cell activity from peripheral blood mononuclear cells with the clinical and pathologic stage of disease in 23 male patients with previously untreated carcinoma of the larynx and 22 healthy male control subjects. Levels of natural killer cell activity against K-562 target cells were similar in control subjects and patients, regardless of stage, tumor size, and clinical cervical adenopathies. Natural killer cell activity, however, was significantly decreased in patients with pathologic cervical lymph node involvement. The number of natural killer cells, as estimated by CD16 and CD56 monoclonal antibodies, was similar in all groups of subjects. We conclude that in patients with laryngeal carcinoma, there is a correlation between deficient natural killer cell activity and nodal metastases, which may represent a prognostic indicator in these patients.
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PMID:Natural killer cell activity in laryngeal carcinoma. 841 47

In order to assess the impact of surgical trauma involved in the therapy of esophageal carcinoma on the cellular immune system, a perspective study was performed involving perioperative hematological parameters. The activity of natural killer cells and the serum concentrations of interleukin-2, interleukin-6 and TNF-alpha were measured in 12 cases of transmediastinal dissection and 10 cases of transthoracic en bloc esophageal resection and compared to values of a control group of thoracic and abdominal surgical patients with non-malignant maladies. Natural killer cells assume a central role in the non-specific immunological response in tumor patients. Their main function is the destruction of tumor cells via cytotoxic activities amplified by the release of interleukin-2 and TNF-alpha. Natural killer cell activity was measured prior to surgery and on postoperative days 4 and 10 using a standardized europium chloride release assay, utilizing K562 target cells. Lymphokines interleukin-2, interleukin-6, and TNF-alpha were also measured on postoperative days 1 and 7 using standardized ELISA assays. The activity of natural killer cells in our patient group sank significantly (P < 0.05) on postoperative day 4 and likewise in the control group and both study groups, activity sank to the original values. In the control group, natural killer cell activity averaged 45% of preoperative values, in comparison with an average of 63% following transmediastinal esophageal carcinoma resection (one cavity procedure), and transthoracic en bloc resection (two cavity procedure). On postoperative day 10, all groups displayed a significant reacceleration of natural killer cell activity (P < 0.05). Whereas transthoracic en bloc resection patients only reached 61% of preoperative values, transmediastinal dissection patients assumed 75%, and 77% was achieved by control group members. Transthoracic en bloc resection of the esophagus led to a more extreme reduction in cytotoxic cellular activity owing to the greater surgical trauma. Suppression of the immunological tumor resistance, especially in the vulnerable perisurgical phase, can have an indirect negative effect on the manifestation risk of hematogenic metastases owing to intraoperative tumor cell dissemination resulting from tumor manipulation and may thus be prognostically relevant.
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PMID:[Effect of surgical trauma on NK cell activity in esophageal carcinoma after transmediastinal dissection vs. transthoracic en bloc resection]. 876 78

Extracts produced from Viscum album L. (mistletoe) as well as certain isolated components are able to stimulate different functions of the immune system. The natural killer cells have been suggested as one of the candidates for direct tumour cell destruction. These cells are defined by their ability to mediate non-major histocompatibility complex (MHC) restricted cytotoxicity without prior sensitization against a specific antigen. However, their effectiveness in tumor defence in vivo is unclear. In general, natural killer cells are unable to lyse fresh autologous tumour cells in vitro unless activated by interleukin-2-preincubation. The results of clinical studies are contradictory, but there is evidence that they may contribute to the prevention of the development of recidives and metastases. In this regard it is interesting that mistletoe extracts are able to stimulate natural killer cell-mediated cytotoxicity in vitro directly as well as indirectly in a cytokine-like manner, with the active components being carbohydrates rather than lectins. Clinical application of mistletoe extracts or isolated lectins is reported to induce augmentation of both number and activity of natural killer cells in peripheral blood in a dose-dependent manner; however, non-responders also have been described. In future work it has to be clarified whether a mistletoe-derived modulation of the natural killer system is of benefit in the tumour defence of cancer patients.
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PMID:Mistletoe therapy for human cancer: the role of the natural killer cells. 917 68

Immunocytokines are antibody-cytokine fusion proteins that combine the unique targeting ability of antibodies with the multifunctional activities of cytokines to activate effector cells in the tumor microenvironment. Here, we demonstrate the therapeutic efficacy of a tumor-specific immunocytokine, huKS1/4-IL2, which effectively inhibited growth and dissemination of lung and bone marrow metastases of human prostate carcinoma in severe combined immunodeficient mice. This antitumor effect was specific and highly effective, irrespective of reconstitution of these mice with human lymphokine-activated killer cells. Survival times of mice treated with huKS1/4-IL2 were increased 4-fold as compared with animals treated with a mixture of the corresponding antibody and recombinant human interleukin-2 (rhIL2). A persistent antitumor response after treatment with the huKS1/4-IL2 immunocytokine in B, T, and natural killer cell-deficient severe combined immuodeficient-BEIGE mice, depleted of granulocytes, implies a major role for macrophages in this treatment effect. Our data demonstrate that immunocytokine-directed interleukin-2 therapy to tumor sites is an immunotherapeutic approach with potent effects against disseminated metastases of human prostate carcinoma and suggest that this treatment could be effective in an adjuvant setting for patients with minimal residual disease.
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PMID:Suppression of human prostate carcinoma metastases in severe combined immunodeficient mice by interleukin 2 immunocytokine therapy. 979 90

We have demonstrated that tumor irradiation enhanced the therapeutic effect of interleukin 2 (IL-2) on pulmonary metastases from a murine renal adenocarcinoma, Renca. To investigate the mechanism of interaction between tumor irradiation and IL-2 therapy, we have histologically evaluated the effects of each therapy alone or in combination on Renca pulmonary metastases. Following treatment of established lung metastases with irradiation and IL-2 therapy, lung sections were processed for H&E or immunohistochemical staining. We found that tumor irradiation or IL-2 therapy locally induced vascular damage, resulting in multifocal hemorrhages and mononuclear cell mobilization in the lung tissue. This effect was amplified in lungs treated with the combined therapy. Immunohistochemistry showed that irradiation produced a macrophage influx into irradiated tumor nodules, and systemic IL-2 therapy induced T-cell infiltration in tumor nodules. Lungs treated with the combined therapy exhibited massive macrophage, T-cell, and natural killer cell mobilization in disintegrating tumor nodules and in the lung tissue. This combined therapy caused a decrease in the number of proliferating tumor cells and an increase in the number of apoptotic cells, which were more marked than with either therapy alone. We suggest that the macrophages mobilized by radiation-induced tissue injury could play a role in phagocytosis of apoptotic tumor cells, processing and presenting of tumor antigens for a systemic immune response activated by IL-2. Tumor destruction may result from the concomitant action of activated T cells, natural killer cells, and macrophages infiltrating the tumor nodules.
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PMID:The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases. 981 31

Based on the knowledge that adenovirus (Ad)-mediated expression of the murine gp75 melanoma antigen (Adgp75) will effectively immunize mice against H2-matched B16 melanoma cells, probably via cell- mediated immune mechanisms, we hypothesized that Ad-mediated delivery of the murine interleukin-12 (IL-12) complementary DNA heterodimer would have independent therapeutic effects on tumor growth, and that the combination of the two vectors would work synergistically to augment the antitumor response. We evaluated the therapeutic effect of each vector alone and in combination for efficacy in C57BL/6 mice with preestablished (2 d) B16 melanoma-derived pulmonary metastases, using the number of lung metastases as the efficacy parameter. Intraperitoneal administration of Adgp75 (10(8) PFU) reduced tumor burden to 45 +/- 7% of controls (P < 0.01), and AdIL12 administration (10(8) PFU, intraperitoneally) reduced the number of metastases to 43 +/- 7% of controls (P < 0.01). The combination of Adgp75 (10(8) PFU, intraperitoneally) and AdIL12 (10(8) PFU, intraperitoneally) provided further protection (15 +/- 3%; P < 0.01 as compared with naive control; P < 0.01 compared with Adgp75 or AdIL12 alone). Mice receiving AdIL12 showed increased natural killer cell (NK cell) function in an in vitro cytotoxicity assay, with a dose- dependent lysis of YAC-1 cells and, to a lesser extent, lysis of B16 cells. To assess the relative contribution of major histocompatibility complex I (MHC I) Dependent and Independent activity in combination therapy with Adgp75 plus AdIL12, we performed adoptive transfer experiments, using splenocytes from mice receiving Adgp75, AdIL12, or Adgp75 + AdIL12, from among which NK cells had been selectively depleted in vitro prior to adoptive transfer. Each group showed significant decreases in tumor burden resembling those with primary treatment. Interestingly, NK-cell depletion from among cells derived from the Adgp75- and AdIL12-treated mice significantly altered the therapeutic response (P < 0.01 compared with the Adgp75 + AdIL12 group), suggesting a significant role of NK-cell-mediated cytolysis in vivo, although there was still a significantly reduced tumor burden (P < 0.01 compared with that of naive controls). Collectively, these data support the concept that the combination of AdIL12 and Adgp75 provides additive effects against pulmonary metastases of B16 melanoma by MHC-independent (NK cell) means as well as MHC-dependent cytotoxic lymphocyte means, suggesting that this therapy may be a useful adjuvant in the treatment of metastatic melanoma.
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PMID:Adenovirus-mediated expression of interleukin-12 induces natural killer cell activity and complements adenovirus-directed gp75 treatment of melanoma lung metastases. 1022 63

Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.
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PMID:Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice. 1035 55


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