Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein previously called "Mr approximately 50/pI approximately 6.9," which we observed to be induced by the immunoregulatory cytokine interferon (IFN)-gamma in human fibroblasts, was purified from a total cell lysate by preparative two-dimensional gel electrophoresis and identified by partial amino-terminal sequencing as leucine aminopeptidase (LAP), a 53-kDa cytosolic exopeptidase. Induction of LAP protein by IFN-gamma, confirmed by immunoblotting with an antiserum raised against bovine lens LAP, is a consequence of induction of LAP mRNA and occurs in all four human cell lines examined: HS153 fibroblasts, ACHN renal carcinoma, A549 lung carcinoma, and A375 melanoma. Induction of LAP mRNA is a secondary response to IFN-gamma, blocked by inhibition of protein synthesis with cycloheximide.
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PMID:Induction of leucine aminopeptidase by interferon-gamma. Identification by protein microsequencing after purification by preparative two-dimensional gel electrophoresis. 155 94

Bryostatin 1, a potent activator of protein kinase C, has antitumor activity against murine lymphoma, leukemia, and melanoma. In vitro, this compound stimulates the release of gamma-interferon, interleukins, and hematopoietic growth factors from accessory cells and activates both T- and B-cells. Bryostatin 1 is also able to stimulate neutrophils to undergo oxidative burst and degranulation. Because of the ability of this compound to stimulate the immune system, cause release of immune mediators, and activate neutrophils, we have examined its effect on bacterial infection by using the gram-negative bacterium Salmonella typhimurium in mice. We find that animals given injections i.v. of S. typhimurium have a shortened life span if they are also given injections i.p. of nonlethal doses of bryostatin 1. There is a dose-response relationship with 100 micrograms/kg bryostatin 1 having a greater effect on survival than 40 micrograms/kg. Below 40 micrograms/kg there are no effects on survival. Analysis of the first 4 h of Salmonella infection demonstrates that bryostatin 1 does not affect the blood clearance of the bacterium. However, by day 2 of infection greater numbers of bacteria are found in the livers and spleens of mice given injections of bryostatin 1. By day 5, 10-fold more S. typhimurium bacteria are found in the livers and spleens of mice receiving 40 micrograms/kg of bryostatin 1. To determine whether bryostatin 1 was affecting growth or causing the death of bacteria, we used a Salmonella carrying a plasmid which has a temperature-sensitive origin of replication and is unable to replicate when the bacteria are in mice. This experiment demonstrates that bryostatin 1 represses bacterial killing but does not affect bacterial growth. Bryostatin 1 given i.p. stimulates a transient syndrome of weight loss and diarrhea from which the mice recover and regain weight, suggesting that bryostatin 1 may release a number of important humoral mediators in vivo. The weight loss is exacerbated by Salmonella infection with mice receiving bryostatin 1 and S. typhimurium, in that they lose approximately 33% of body weight prior to death. Thus, at doses used to treat murine tumors, bryostatin 1 treatment does not affect the clearance of S. typhimurium from the blood but does decrease the killing of bacteria in the liver and spleen, leading to early animal death. Such potential effects of bryostatin 1 on the outcome of bacterial infections should be evaluated in ongoing human trials of this agent.
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PMID:In vivo administration of bryostatin 1, a protein kinase C activator, decreases murine resistance to Salmonella typhimurium. 155 18

Three patients with metastatic malignant melanoma, 2 of whom were males with primary lesion on the shoulder, and a female with primary lesion on the ankle, with Clark's level III-IV, completely responded to interferon-DTIC, but failed in the brain. Radiologically, all the lesions were peripheral in location, and none showed any bleeding tendency. Clinically, these lesions seemed to be resistant to radiotherapy, chemotherapy or steroid treatment, and were the cause of death after a very short survival period. Interferon apparently is inactive against melanoma brain metastases, but does cause CNS symptoms. Because CNS metastases are sometimes the sole site of clinical relapse, and are frequently disabling, prophylactic cranial irradiation (PCI) needs to be studied in high risk patients.
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PMID:Brain metastases of malignant melanoma in interferon complete responders: clinical and radiological observations. 156 Feb 59

In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35-40% of cases and partial remission in a further 35-40%. Mild or moderate limb toxicity is usual, but severe toxic reactions in the limb sometimes occur. After preliminary reports suggested that cisplatin administered by ILP was even more effective than melphalan yet less toxic, a study was undertaken to further assess the value of hyperthermic ILP with cisplatin in the management of limb melanoma. Ten patients were treated. The procedure failed to eliminate melanoma in the limb in 5 of the 6 who received therapeutic ILPs for recurrent disease, and recurrence developed in 2 of the 4 patients who received prophylactic ILPs. Toxicity in the perfused limbs was unacceptably high, with 2 of the 10 patients having severe reactions, one necessitating amputation. We conclude from the results of this study and from a review of literature that neither cisplatin nor any other drug or drug combination so far used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan. Studies are currently in progress investigating double perfusion protocols, new strategies with regional hyperthermia, and the administration by ILP of biological response modifiers such as tumor necrosis factor and interferon. However, for the present, hyperthermic ILP with melphalan remains the treatment most likely to be successful in eliminating or controlling advanced or recurrent melanoma in a limb.
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PMID:Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. 156 3

Twenty-one patients with disseminated malignant melanoma received recombinant tumor necrosis factor (TNF), 150 micrograms/m2 intravenously on days 1-5 every 2 weeks for four cycles and then every 3 weeks. Recombinant TNF produced no meaningful palliation. One patient (5%) attained an objective response of nodal, but not visceral, disease, which lasted 3 weeks. The median time to progression was 4 weeks. The median survival was 7.7 months. Ninety percent of patients developed mild to severe cytokine "flu." Ten percent developed significant hepatic toxicity (AST greater than 3 times normal). As a single agent, recombinant TNF is not likely to palliate disseminated malignant melanoma. However, combinations of recombinant TNF and cytotoxic or immune modulatory agents, particularly gamma interferon, may merit further investigation.
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PMID:Phase II trial of recombinant tumor necrosis factor in disseminated malignant melanoma. 159 Feb 81

Interleukin-2 (IL-2) therapy generates killer cells with major histocompatibility complex (MHC)-unrestricted cytotoxicity against most tumors but not normal tissues. Cyclosporine A (CsA) has been reported to break tolerance to self and to induce killer cells with specificity against class II MHC (Ia) antigens both on the host and the tumor cells, resulting in a mild graft-versus-host disease (GVHD) in an autologous bone marrow transplantation (BMT) setting in the rat. We used these two agents in a syngeneic BMT model in a strain of mice that does not develop GVHD with CsA. Therapy with either agent alone was ineffective, whereas a combination of CsA plus IL-2 after BMT induced a potent graft-versus-tumor (GVT) effect against a melanoma and an acute myeloid leukemia. The antitumor effect could be adoptively transferred by infusing spleen cells harvested from mice treated with CsA plus IL-2 into secondary recipients that received chemoradiotherapy. The cytotoxicity of these cells was not influenced by treatment of tumor cells with gamma-interferon or Ia antibody. The cytotoxic effect was mediated by Thy 1+ and asialo GM 1+ cells. There was no GVHD either in the primary recipients of CsA and IL-2 or in those receiving the adoptively transferred spleen cells. Our findings show that combination therapy with CsA and IL-2 after syngeneic BMT induces a potent GVT effect in a non-MHC-restricted manner, and point to the existence of differences between the mechanisms of GVT and GVHD.
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PMID:Synergism of interleukin-2 and cyclosporine A in induction of a graft-versus-tumor effect without graft-versus-host disease after syngeneic bone marrow transplantation. 161 Oct 84

The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.
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PMID:Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial. 162 72

There is a theoretical basis for the synergy of interleukin-2 (IL-2) with other cytokines. We have investigated sequential treatment with IL-2 and alpha interferon. 1 of 22 patients with metastatic renal cell carcinoma had a partial response and one a minimal response to continuous infusion IL-2 but none of the 9 patients with melanoma responded. 16 of 17 patients with renal cell cancer, and 8 with melanoma, were then treated with alpha interferon. 2 patients with renal cell cancer responded to alpha interferon with sustained remissions of 30 and 40 months; both had responded to IL-2. The investigation of combination therapy with other cytokines is suggested, by these unusually long responses to alpha interferon.
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PMID:Sequential interleukin-2 and alpha interferon for renal cell carcinoma and melanoma. 162 71

The sensitivity and resistance of six human melanoma cell lines to gamma-interferon (gamma-IFN) and tumour necrosis factor-alpha (TNF-alpha) have been examined. Amelanotic cell lines were more sensitive to gamma-IFN and TNF-alpha than melanotic cells. The cytotoxicity of gamma-IFN and TNF-alpha could be reversed in all cells by the addition of L- or D-tryptophan to the culture medium. Melanoma cells resistant to gamma-IFN excrete calcium activated neutral protease (CANP) and as a consequence, make L-tryptophan available by the hydrolysis of serum proteins in the culture medium. Resistance to gamma-IFN could be reversed by the addition of specific CANP inhibitor, whereas gamma-IFN-sensitive strains became more resistant with the addition of CANP to the culture medium. It has been confirmed that gamma-IFN induces indoleamine 2,3-dioxygenase in melanoma cells. This enzyme utilizes the superoxide anion (O2-) as a substrate for the oxidation of either L- or D-tryptophan to N-formylkynurenic acid leading to cell death. The induction of this degradative pathway for L-tryptophan kills cells by starvation of this essential and relatively scarce amino acid. TNF-alpha induces manganese-containing superoxide dismutase (MnSOD) which also uses O2- to produce cytotoxic concentrations of hydrogen peroxide. Therefore, it can be concluded that the cytotoxicity of both gamma-IFN and TNF-alpha depends on the availability of L-tryptophan as the substrate for the removal of O2- via indoleamine 2,3-dioxygenase.
Melanoma Res
PMID:Tryptophan protects human melanoma cells against gamma-interferon and tumour necrosis factor-alpha: a unifying mechanism of action. 166 25

Administration of interferon as a single therapeutic regimen in cancer patients with various neoplasias has had only limited efficacy in ameliorating the negative clinical course of their disease. In the present study, we have evaluated the effect of recombinant human fibroblast (IFN beta) and immune (IFN gamma) interferon, alone and in combination, on growth, differentiation and the expression of class I and II histocompatibility locus antigens (HLA) and melanoma-associated antigens on the human melanoma cell line H0-1. The effect of combinations of interferons on the antigenic profile of human melanoma cells displaying different organ colonization and spontaneous metastatic potential in athymic nude mice was also determined. H0-1 cells were more sensitive to the antiproliferative activity of IFN beta than to IFN gamma and the combination of interferons resulted in a potentiation of growth suppression. The antiproliferative effect of both interferons was greater in later-passage than in earlier-passage H0-1 cells, possibly reflecting alterations in the evolving tumor cell population as a result of long-term in vitro propagation and/or the selective outgrowth of cells with an increased growth rate. The enhanced growth suppression observed in H0-1 cells treated with the combination of IFN beta plus IFN gamma was not associated with a significant increase in the level of melanin, a marker of melanoma differentiation, above that observed with either interferon used alone. IFN beta and IFN gamma differentially modulated the expression of class I and II HLA and melanoma-associated antigens in H0-1 cells and a series of melanoma cells with different organ colonization and metastatic potential, including MeWo, MeM 50-10, MeM 50-17, 3S5 and 70W. No consistent potentiation or antagonism in the expression of any specific antigen was observed in any of the melanoma cell lines exposed to the combination of interferons. The present study demonstrates that the combination of IFN beta plus IFN gamma can potentiate growth suppression in H0-1 human melanoma cells and that this effect is not associated with an increase in differentiation or a potentiation in antigenic modulation. In addition, no direct correlation between the expression of any specific antigen or its modulation by IFN beta or IFN gamma, alone or in combination, and organ colonization and metastatic potential in nude mice was observed in the different melanoma cell lines.
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PMID:Potentiation of growth suppression and modulation of the antigenic phenotype in human melanoma cells by the combination of recombinant human fibroblast and immune interferons. 167 7


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