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 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

Kupffer cells (KC) are believed to play a major role in protecting the liver from metastases. In vitro, activated KC mediate both tumor cell cytostasis and cytolysis. Because hepatocytes (HC) occupy a position adjacent to KC in vivo, we investigated the influence of HC on KC tumoricidal activity. Using an in vitro assay of KC-mediated tumor cell cytostasis against murine P815 mastocytoma cells, we found that the presence of HC in the culture profoundly increased KC tumoricidal activity. HC enhanced KC inhibition of P815 proliferation and lowered the concentration of lipopolysaccharide and interferon-gamma necessary to activate the KC to a tumoricidal state. This stimulatory HC effect was dependent on the number of HC present and was transferable in cell-free supernatants, indicating that it was mediated by a soluble secreted product of HC. Furthermore, unlike other macrophage-priming or -potentiating factors, the transferable HC factor(s) was effective only if added simultaneously with lipopolysaccharide or interferon-gamma and not effective if added before these activating agents. These data show that HC produce a soluble mediator that enhances KC tumoricidal activity, suggesting that HC and KC interactions may be critical to the antitumor defense mechanisms of the liver.
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PMID:Hepatocytes enhance Kupffer cell-mediated tumor cell cytostasis in vitro. 250 99

The purpose of this study was to examine the effective anti-metastatic activity by multiple i.v. administrations of mouse recombinant interferon-gamma (IFN-gamma) against pulmonary metastases of 3LL or B16-BL6 melanoma cells after surgical excision of primary tumors. Multiple treatments with IFN-gamma reduced effectively the incidence of pulmonary tumor metastases. Repeated 4 consecutive treatment modalities with IFN-gamma showed remarkable reduction of lung tumor colonies, and also rendered alveolar macrophages (AM) cytotoxic against B16-BL6 cells. In contrast, 14 consecutive administrations of IFN-gamma at any doses (10(2) and 10(3) U/mouse) could not activate macrophages to become cytotoxic, but were effective in regressing metastases. Thus, antimetastatic activity of IFN-gamma may be due to the stimulation of host immune defense systems such as induction of tumoricidal macrophages, presumably the direct antiproliferative action to tumor cells, or both actions under the appropriate administration conditions. We found that the systemic administration of IFN-gamma under appropriate multiple treatment modalities results in the reduction of the lung metastases and can activate AM to become tumor cytotoxic at relatively low doses (10(2) U). High-dose IFN-gamma in the multiple administration schedule was also effective for the reduction of lung tumor colonies, but strongly suppressed the nonspecific immune function and could not activate tumoricidal properties of AM.
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PMID:Effect of systemic administration of mouse recombinant interferon-gamma on the lung tumor metastases in mice. 251 71

A new cell line (CCA) was established from a human embryonal rhabdomyosarcoma. It showed an "early" myogenic differentiation pattern: vimentin expression was found in 100% of cells, desmin in about 40% and myosin of the embryonic isoform in about 5%. Class I HLA expression on CCA cells was undeterctable but was greatly increased by in vitro treatment with human recombinant interferon-gamma and only marginally increased by human recombinant tumour necrosis factor-alfa. CCA cell line was tumorigenic in nude mice after either subcutaneous or intramuscular injection; macroscopic spontaneous metastases were not detected. The ability to induce metastatic nodules in the lungs was found when CCA cells were injected intravenously in cyclophosphamide-pretreated nude mice and, at low frequency, in untreated nude mice.
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PMID:Metastatic ability and differentiative properties of a new cell line of human embryonal rhabdomyosarcoma (CCA). 251 17

We examined the activities of activated lymphocytes, interferon-gamma (IFN-gamma), and interleukin 2 (IL-2) in adoptive immunotherapy of pulmonary metastases. Pulmonary metastases produced in Balb/c mice by a single tail-vein injection of 5 X 10(5) murine sarcoma (MCB8) tumor cells on day 0 were treated with combinations of Con A-activated lymphocytes (CAL) (3 X 10(7) cells on days 3 and 7), IL-2 (5 X 10(4) U three times a day on days 3 to 8), and IFN-gamma (5 X 10(4) U/mouse on days 1 to 8). Treated tumors contained increased numbers of infiltrating Thy-1.2+ lymphocytes and a predominance of L3T4+(CD4+) lymphocytes. The level of expression of class I and class II MHC antigens by tumor cells in the lung was increased after treatment. Mice that received CAL + IL-2 + IFN-gamma showed approximately 80% reduction in tumor burden as compared to controls (P = 0.001). Mice treated with IL-2 + CAL, or IL-2 + IFN-gamma, displayed approximately 50% reduction (both P less than 0.02 as compared to triple therapy), whereas IL-2, IFN-gamma, or CAL administered as single agents had little effect on pulmonary metastases. We conclude that adoptive immunotherapy with activated lymphocytes and IL-2 is enhanced by IFN-gamma.
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PMID:Adoptive immunotherapy of murine pulmonary metastases with interleukin 2 and interferon-gamma. 251 74

We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.
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PMID:Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. 308 21

The antitumor effect of recombinant human interferon-beta (r IFN-beta) and recombinant interferon-gamma (r IFN-gamma) was studied in vivo using a pulmonary metastatic model involving nude mouse human colon cancer xenografts. The results indicated that both r IFN-beta and r IFN-gamma had an inhibitory effect on pulmonary metastases. Furthermore, a combination of r IFN-beta and r IFN-gamma acted synergistically in the inhibition of pulmonary metastases. These results suggested that a combination of r IFN-beta and -gamma could be a most effective form of interferon therapy for cancer.
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PMID:[Synergistic effect of recombinant human interferon-beta and -gamma on human colon cancer transplanted into nude mice]. 309 15

Human blood monocytes from healthy volunteers, separated by centrifugal elutriation, were not cytotoxic to allogeneic A 375 melanoma cells. The monocytes were rendered tumoricidal by incubation for 24 h with natural interferon-alpha and beta or recombinant interferon-alpha A and alpha A/D (more than 100 U/ml) or with interferon-gamma (more than 1 U/ml). Liposome-MTP-PE at concentrations of more than 50 nmol/ml also induced tumoricidal activity of monocytes. When a combination of subthreshold concentrations of these IFNs and liposome-MTP-PE were added to monocyte cultures, IFN-alpha and beta acted additively in monocyte activation, while IFN-gamma acted synergistically. The synergism for monocyte activation required that monocytes be incubated first with IFN-gamma and then with liposome-MTP-PE. These findings suggest that the synergistic effect of IFN-gamma and liposome-MTP-PE can decrease the necessary clinical doses of these agents for malignant diseases, and may have therapeutic availability in the treatment of metastatic cancer in humans.
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PMID:[Induction of tumoricidal properties in human monocytes by synergism between interferon-gamma and liposome-entrapped muramyl tripeptide]. 309 16

We report a clinical study of toxicity and pharmacokinetics of intravenously administered natural interferon-gamma. Twenty three cases with metastatic cancer were given interferon-gamma at doses of 10 X 10(4)-400 X 10(4) IU in single injection. Another twenty three cases were administered at doses of 5 X 10(4)-50 X 10(4) IU/day every day for thirty days. Side effects associated with natural interferon-gamma administration were qualitatively similar to those previously reported for alpha, and beta interferon treatment. After intravenous injection, interferon-gamma was cleared monoexponentially with a short half-life of 120 minutes from the circulation. One case with disseminated thyroid cancer showed minor response.
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PMID:[Phase I study of natural interferon-gamma]. 311 41


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