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)

We studied the phenotype and antitumor cytolytic activity of splenocytes from mice with K-1735 pulmonary metastases and tumor-infiltrating lymphocytes (TILs) from these metastases following treatment with anti-CD3, IL-2, and TNF combination immunotherapy. Mice were injected with 5 x 10(4) tumor cells and received a single 5 micrograms i.p. dose of anti-CD3 on day 3, followed by either IL-2 alone or fourfold less IL-2 with TNF (25,000 U/day) given at 3-day intervals. A single dose of anti-CD3 followed by low-dose IL-2 and TNF caused the greatest reduction in metastases compared to anti-CD3 alone, higher doses of IL-2 alone, or IL-2 + TNF. Reduction in metastases (greater than 80%) using the three agents was equal to or exceeded that achieved by ninefold higher concentrations of IL-2 alone. Treatment with anti-CD3 + IL-2 and TNF significantly prolonged survival, and resulted in 60% of mice achieving long-term survival greater than 120 days. This was superior to single agents or other combinations with the three agents causing a synergistic rather than additive effect. The anti-CD3-activated splenocytes were a heterogeneous population of T cells, with an increased number of CD8+ cells compared to splenocytes from mice treated with high doses of IL-2 alone. Analysis of TILs showed a greater proportion of CD8+ cells in anti-CD3-treated mice compared to IL-2 alone, but a lower proportion of CD4+ cells. Lymphokine-activated killer (LAK) and natural killer (NK) activities of both splenocytes and TILs in vitro increased following anti-CD3/IL-2 + TNF treatment, and were consistently greater than that generated with four times more IL-2 alone. TNF appeared to potentiate cytolytic activity rather than affect phenotypic changes. These results indicate that the sequential use of anti-CD3, IL-2, and TNF for LAK induction and maintenance potentiates antitumor activity, and suggests novel strategies for combination immunotherapy.
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PMID:Phenotype and cytolytic activity of mouse tumor-bearer splenocytes and tumor-infiltrating lymphocytes from K-1735 melanoma metastases following anti-CD3, interleukin-2, and tumor necrosis factor-alpha combination immunotherapy. 179 Jan 40

Fifteen patients with therapy-resistant liver metastases were treated in a phase-I study with recombinant human TNF (rTNF). The rTNF was injected into one liver metastasis by ultrasound guidance, using a 50 microgram escalating dose schedule (3 patients/dosage) ranging from 100-350 micrograms/injection. Influenza-like symptoms like fever, chills, nausea and vomiting were the main clinical side effects. Two patients, treated concomitantly with rTNF and morphine, showed mild hypotension. Other toxicities, as reported after systemic use of rTNF, such as decrease in leukocyte and platelet counts, renal or liver toxicity were not observed. In eight patients growth arrest was observed in rTNF-treated metastases, whereas non-injected lesions showed growth progression. The maximum tolerated dose by this route of administration is greater than 350 micrograms/injection. Based on these observations it is concluded that the toxicity of rTNF injected into liver metastases by sonographic control is transient and mild and that intratumoural administration of rTNF might play a role in local tumour control.
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PMID:Local treatment of liver metastases with recombinant tumour necrosis factor (rTNF): a phase one study. 194 89

We analyzed the expression of class-I antigens in ex vivo human tumor cells by isoelectric focusing (IEF) the anti-class-I mAb W6/32 immunoprecipitates prepared from cell lysates. Out of 42 experiments, 27 were technically successful. The patient's blood lymphocytes were used as controls. In vitro exposure of the tumor cells to IFN gamma and TNF alpha elevated class-I antigen expression. In 11 cases, defects in MHC-class-I-antigen expression were observed. In 2 cases the antigens were detected only in the cytokine-treated tumor samples, probably due to a defect in the association between beta 2m and class-I heavy chains. Selective changes in the expression of alleles were seen in 10 cases and might involve HLA A, B and C antigens. Alterations in class-I expression as compared with the lymphocytes were observed in 9 of 13 cases in which the tumor cells were collected from metastases, and only in 2 of 14 primary tumors.
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PMID:Expression of MHC-class-I antigens in human carcinomas and sarcomas analyzed by isoelectric focusing. 206 76

The effects of recombinant tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on B16 mouse melanoma experimental metastatic ability and major histocompatibility complex (H-2b) antigens expression were studied. B16 cells exposed in vitro to TNF-alpha had an increased H-2 expression and were more metastatic than untreated cells. The simultaneous treatment with TNF-alpha and IFN-gamma amplified the enhancement of experimental metastasis and all other effects obtained with TNF-alpha alone. The B16 clone B78H1, selectively resistant to H-2 induction and to enhancement of metastatic ability by IFN-gamma, was not affected by treatment with TNF-alpha and with TNF-alpha + IFN-gamma. These findings contribute to a better understanding of the pleiotropic effects of TNF, some of which can have opposing actions in the complex tumor-host relationships.
Clin Exp Metastasis
PMID:Enhancement of experimental metastatic ability by tumor necrosis factor-alpha alone or in combination with interferon-gamma. 210 93

We have evaluated the effects of combinations of various cytokines on the reconstitution of natural killer (NK) cell activity and resistance to metastases from B16 melanoma, in lethally irradiated mice transplanted with syngeneic bone marrow. Treatment with some combinations of interleukin-2 (IL-2) and other cytokines (IL-2 + IL-1 + TNF alpha or IL-2 + IL-1 + LT) induced appreciably greater and more rapid augmentation of NK cell regeneration than IL-2 alone, as measured in vitro in the 4-h 51Cr release assay against YAC-1 or in vivo in an assay of lung clearance of 125IUdR-labeled tumor cells. The same treatments also induced significant augmentation of in vivo resistance against pulmonary metastases in C57BL/6 mice injected with B16 melanoma cells. These data indicate that stimulation of NK activity in tumor-bearing bone marrow transplanted recipients may be of value in the control of metastatic disease.
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PMID:In vivo effects of cytokines on development of natural killer cells and antitumor activity in lethally irradiated bone marrow transplanted recipients. 218 Oct 70

Tumor cell variants were derived from an AKR T-cell lymphoma cell line (BW5147, H-2k haplotype). These variants differed in their malignant potential and in their membrane expression of class I MHC antigens. High tumorigenic and spontaneous metastatic capacity was found to be predominantly associated with a decrease of H-2Kk class I major histocompatibility complex (MHC) antigen expression. In contrast, high experimental metastatic capacity correlated strongly with an increased H-2Dk antigen expression. The in vitro invasive potential and the LFA-1 expression of the BW variants showed no correlation with the differential MHC antigen expression and the differential metastatic and tumorigenic capacity of the BW variants. Furthermore, the susceptibility of the BW 5147 variants to TNF and NK-mediated cytotoxicity was not related to the differential metastatic potential and the expression of the class I MHC antigens.
Invasion Metastasis 1990
PMID:Association between MHC class I antigen expression and malignancy of murine T lymphoma variants. 230 62

We have investigated the endogenous production of a serum cytotoxic factor when recombinant interferon-gamma (rIFN-gamma) is combined with synthetic lipid A subunit analogs of low toxicity (GLA compounds). The cytotoxic activity of the serum was measured by the crystal violet staining method with L929 cells as a target. Intravenous administration of rIFN-gamma followed by intravenous administration of lipopolysaccharide induced the endogenous production of a cytotoxic factor in the serum. The priming effect of rIFN-gamma appeared immediately and persisted for approximately 20 h after the injection. Administration of lipopolysaccharide as a trigger enhanced the production of the cytotoxic factor in the serum maximally 2 h after the injection. The cytotoxic activity in the serum was completely inhibited by anti-(mouse tumor necrosis factor) (TNF) antibody. A synthetic lipid A subunit analog (GLA-60), which is much less toxic in its endotoxin activities than lipopolysaccharide or synthetic lipid A (compound 506), induced the endogenous production of serum TNF in rIFN-gamma-primed mice. GLA-60 entrapped within liposomes induced the production of serum TNF in rIFN-gamma-primed mice more effectively than GLA-60 solubilized in phosphate-buffered saline. Intravenous or intranasal administrations of rIFN-gamma followed by intranasal administration of GLA-60 produced TNF in the lung washing fluid but not in the serum, indicating that TNF production can be induced locally rather than systemically by the alteration of the administration route of the primer and trigger. These results indicate that GLA-60, a lipid A subunit analog of low toxicity, is a beneficial triggering agent in the production of endogenous TNF, as well as having other immunopharmacological properties, and may provide a basis for cancer (metastases) treatment as a result of its ability to induce endogenous TNF.
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PMID:Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-gamma combined with a lipid A subunit analog (GLA-60) of low toxicity. 249 79

Combinations of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) demonstrate synergistic antiproliferative activity in vitro. Therefore, we initiated a clinical study of recombinant TNF-alpha (rTNF-alpha) and rIFN-gamma combination therapy in humans. Twenty-five patients with metastatic cancer received both rTNF-alpha and rIFN-gamma by intramuscular injection for 5 consecutive days every 2 weeks for a total of 4 weeks. The dose levels were 5/5, 10/5, 10/10, 25/10, 25/25, 50/25, 50/50, 75/50, and 75/75 micrograms/m2 per day of rTNF-alpha/rIFN-gamma. A minimum of 2 patients were entered sequentially at each dose level. If the first 2-week cycle of therapy was well tolerated, the dose was increased to the next highest dose level during the second 2-week cycle. Fever, chills, and fatigue were observed at all doses. Severity of symptoms corresponded to increasing dose levels. Although TNF is identical to a molecule known as "cachectin," the vast majority of our patients did not lose weight while on study. However, alterations in lipid metabolism occurred and were manifested by a median change in triglyceride values of +40 mg/dl (range, -130 to +318 mg/dl), and in cholesterol values of -30 mg/dl (range, -103 to +2 mg/dl). The maximum tolerated dose was 75 micrograms/m2 of rTNF-alpha combined with 50 micrograms/m2 of rIFN-gamma, with dose-limiting side effects being mainly constitutional symptoms. A dose-related suppression in granulocyte and platelet counts was observed. Hematologic parameters returned to baseline within 72 h after therapy was discontinued, and neither infection nor bleeding occurred. Ten of 22 evaluable patients had stable disease for a median of 8 weeks (range, 4-21 weeks); 12 patients showed progressive disease. This study will form the framework for phase II trials of rTNF-alpha and rIFN-gamma combination therapy.
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PMID:Phase I study of a combination of recombinant tumor necrosis factor-alpha and recombinant interferon-gamma in cancer patients. 250 84

NK cells play an important role in fighting tumor metastases. The incidence of metastasis was found to increase in mice with low cytotoxicity of NK cells. In the mice with high cytotoxicity of NK cells, the incidence of metastasis decreased. LAK cells induced by IL2 mediate the regression of established metastases from a variety of tumors. LAK progenitor cells were predominantly found in CD3-CD16+ Leu19+ fraction, a subset that are known to be the NK cells. Thus, NK cell lineage in LAK cells plays an important role for the inhibition of tumor metastases. Cells having NK cell-like phenotype nature, however, also play a key role in the side effects of adoptive immunotherapy involving IL2. In order to decrease adverse side effects during therapy, we are currently testing combination therapy of LAK cells plus IL2, IL2 alone with IFN, TNF, BRM, indomethacin and so on. Overall, augmentation of NK cells is one of the significant therapeutic methods to prevent metastases.
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PMID:[Role of NK cells in lung metastasis immunosurveillance]. 265 17

A nude mouse renal subcapsular and subcutaneous implantation xenograft model utilizing the SN12C human renal carcinoma cell line was investigated. In the absence of treatment, renal subcapsular implantation of SN12C resulted in metastatic spread (lung, liver and lymph nodes) and death of all animals. Radical nephrectomy of the tumor-bearing kidney after various periods of tumor implantation demonstrated that surgery alone after 18 days of tumor growth resulted in no statistically significant increase in survival with 100% of the nephrectomized animals succumbing to local recurrence and distant metastases. Recombinant human tumor necrosis factor (rTNF) and VP16 (etoposide), both well known cytotoxic and cytostatic anticancer agents, were tested singly and in combination against this metastatic model of human renal adenocarcinoma. Single agent rTNF or VP16 therapy after radical nephrectomy demonstrated only minimal efficacy with no significant decrease in local recurrence and distant metastases as compared to nephrectomy only control animals. In contrast, the combination of rTNF plus VP16 when given after nephrectomy resulted in a significant decrease in local recurrence and no gross evidence of metastasis in any animal. Subcutaneously growing SN12C tumor nodules were also treated with the same rTNF, VP16 and combination regimens. Regression in tumor size was noted only in the combination treatment group. rTNF or VP16, as single agents, demonstrated only slight growth inhibition that was not statistically significant. These results suggest that by combining TNF plus VP16, a synergistic enhancement of antineoplastic activity against local as well as metastatic human renal cell carcinoma can be produced.
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PMID:Enhanced anti-tumor effects of recombinant human tumor necrosis factor plus VP-16 on metastatic renal cell carcinoma in a xenograft model. 273 97


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