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)

Interleukin-2 has demonstrated significant and consistent activity against melanoma even in patients who have been treated previously with other modalities. This paper reviews local treatment, systemic treatment with single-agent, combination, and high-dose chemotherapy, and new agents; biologic modifier therapy, including tumor vaccines and active specific immunization, and interferons; and recombinant interleukin-2, which has activity when used alone, with lymphokine-activated killer cells, chemotherapy, or biologic modifiers. Tumor response, predictors of response, and survival are also discussed.
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PMID:Recombinant interleukin-2 and other types of treatment of advanced malignant melanoma. 206 98

Interleukin-2 is a lymphokine with documented antineoplastic influence, with not completely understood mechanism of action. The case of 46-years old patient with relapsed metastatic malignant melanoma treated with constant-infusion of rIL-2 is described. 9-month remission was achieved. During the course of treatment a lot of side effects including flu-like symptoms, hypotonia, anemia and thrombocytopenia, and also many biochemical disturbances were observed.
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PMID:[Interleukin-2 in the treatment of malignant melanoma. A case report]. 207 26

The induction and activation of autologous cytotoxic cells (lymphokine activated killer cells = LAK) by interleukin-2 (Il-2) is an interesting new approach in cancer treatment. So far, Il-2 alone or in combination with the transfer of in vitro activated LAK (adoptive immunotherapy = AI) was shown to be effective predominantly in renal cell cancer and malignant melanoma with a response rate of 20-35%. The results in colorectal tumors are disappointing. Clinical experiences with Il-2 in other tumor entities are limited and/or mostly lack sufficient responses. To improve therapeutic results and to reduce the serious side effects, present trials focus on combinations of Il-2 with other cytokines, predominantly interferon-alpha (IFN-alpha), or chemotherapy. So far, the combination of Il-2 + IFN-alpha seems to be at least as effective as Il-2 + AI in renal cell cancer. Combinations of chemotherapy and Il-2, especially in gastrointestinal tumors, have not been shown to exceed the moderate results of chemotherapy alone so far. Trials with highly activated or specific cytotoxic cells as tumor-infiltrating lymphocytes (TILs) or adherent-LAK-cells are still more experimental. The value of IL-2 for elimination of minimal residual disease in acute leukemias after autologous bone marrow transplantation or as consolidation of complete response will have to be defined. The present paper reviews clinical studies with Il-2 in malignancies and its significance for therapeutic approaches.
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PMID:The clinical significance of interleukin-2. 209 77

Interferon-gamma (IFN) and tumor necrosis factor-alpha (TNF) were examined for their ability to enhance major histocompatibility complex (MHC) expression on a variety of human tumor and normal tissue targets. Enhanced expression of MHC correlated with decreased target susceptibility to lysis by fresh peripheral blood mononuclear cells (PBMCs) and IL-2-augmented PBMCs (aPBL) but not as clearly with cells with lymphokine-activated killer (LAK) activity. These studies revealed maximal MHC enhancement after 48-72 h of incubation in IFN. Resistance to lysis by natural killer (NK) cells was best demonstrated after 72 h. Further, IFN and TNF were synergistic in their effects on MHC expression and induction of resistance of the cultured leukemias K562 and Molt-4 to aPBL effectors. Conversely, LAK susceptibility was usually unaltered after target IFN and TNF treatment. Incubation of fibroblasts and vascular endothelial cells with IFN also consistently resulted in MHC class I enhancement and resistance to NK lysis, whereas LAK susceptibility was variably affected. The brief incubation of fresh PBL in IL-2 (4-6 h) resulted in effectors highly lytic toward cultured cells, but with no activity against fresh tumor. Cultured cell lines treated with IFN and TNF were rendered relatively resistant to lysis by these activated cells. Fresh tumor MHC expression and LAK susceptibility was unchanged after IFN incubation. Additionally, there was no correlation between the level of MHC class I or class II expression and LAK susceptibility to any fresh, uncultured melanoma studied. These data suggest that LAK effectors possess different mechanisms of tumor recognition or lysis than cells with NK activity or cells briefly incubated (4-6 h) in IL-2. The ability of tumor-infiltrating lymphocytes to lyse the cultured autologous tumor target was markedly increased by preincubation of the targets with IFN and TNF. Finally, it appears that IL-2 treatment and the resultant endogenous production of IFN by T-lymphocytes should not adversely affect tumor susceptibility to current immunotherapy using IL-2.
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PMID:Cytokines alter target cell susceptibility to lysis: I. Evaluation of non-major histocompatibility complex-restricted effectors reveals differential effects on natural and lymphokine-activated killing. 211 73

In order to identify novel mediators synthesized in activated macrophages, a cDNA library was prepared from cultures of the mouse macrophage cell line RAW 264.7 that had been treated with lymphokine-rich conditioned medium from mitogen-stimulated mouse spleen cells. Differential plaque hybridization identified a cDNA, designated m119, that detected a 1.6-kilobase mRNA that accumulated in response to gamma-interferon (IFN-gamma) but not in response to other macrophage activators, including IFN-alpha, IFN-beta, and lipopolysaccharide. The mRNA encoded a predicted protein of Mr 14,461 containing a 21-amino acid signal peptide. The primary structure of the predicted protein indicated that it is a member of a recently described family of cytokines related to platelet factor 4, including Gro/melanoma growth stimulatory activity and neutrophil-activating peptide/interleukin 8. The selective induction of the m119 mRNA by IFN-gamma that the predicted m119 protein mediates a macrophage activity regulated by IFN-gamma. The m119 protein may be a cytokine that affects the growth, movement, or activation state of cells that participate in immune and inflammatory responses. It is proposed that the gene encoding this protein be called mig, for monokine induced by gamma interferon.
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PMID:A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines. 211 67

We have shown that a murine CD4+ PPD-reactive T lymphocyte clone was weakly cytotoxic towards the syngeneic tumour B16 melanoma and MC6A fibrosarcoma which had been coated with PPD using a monoclonal antibody-PPD heteroconjugate. Cell-free supernatants produced by PPD-stimulated T lymphocyte clones were however highly cytostatic for the two tumour targets when assayed over 48-72 h. In this study we have demonstrated good titres of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) in the supernatants, which accounted for their observed cytostatic activity on the tumour targets. The high level of cytostasis seen with the B16 melanoma using the supernatants could be attributed to their sensitivity to the cytostatic activity of IFN-gamma; the lower levels of cytostasis seen with the IFN-gamma-resistant MC6A target was the result of IFN-gamma increasing the sensitivity of this target to TNF. Antibodies to IFN-gamma were able to neutralize the majority of the cytostatic activity of the supernatants on both targets, consistent with the role demonstrated for this lymphokine.
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PMID:Cytostasis of different tumours by a murine PPD-reactive CD4+ T lymphocyte clone is mediated by interferon-gamma and tumour necrosis factor alone or synergistically. 212 29

Adoptive immunotherapy for the treatment of cancer has met with limited but, for some, encouraging success. A minority of malignant melanoma and renal cell carcinoma patients respond to therapy with interleukin 2 (IL-2) or IL-2 plus lymphokine-activated killer (LAK) cells. The mechanism of response, and the reasons for the variation within disease groups, is not clear. In this article, Giorgio Parmiani proposes that successful adoptive therapy is dependent on the recruitment of activated host antitumor T lymphocytes and suggests that this explains the greater efficacy of tumor-infiltrating lymphocytes in combating melanoma and renal cell carcinoma.
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PMID:An explanation of the variable clinical response to interleukin 2 and LAK cells. 218 66

Tumor-infiltrating lymphocytes (TILs) have shown in vivo antitumor efficacy in both animal and human studies. Functions thought necessary for antitumor activity include cytolysis, homing, and proliferation at tumor sites. TILs, which are T lymphocytes grown ex vivo directly from tumors, bear interleukin 2 (IL-2) receptors capable of transducing the IL-2 mitogenic signal. However, IL-2 is not normally synthesized by solid tumor cells. This study was aimed at exploring the possible presence of T-cell mitogens of tumor origin. To this end four TIL lines derived from four melanoma patients were studied for their ability to use the environments of cultured tumor cell lines as mitogenic sources. The presence of four irradiated cultured human tumor cell lines, three of which were derived from the same melanoma patients as the TILs, were found to stimulate proliferation of human TILs in the absence of IL-2. Further investigation showed that the observed proliferative stimulation by the fourth tumor line was due to secreted factor(s) as mitogenic activity was present in the serum-free tumor cell supernatant. Both immunologic analyses of this medium and proliferative assays in which TILs were stimulated with recombinant lymphokine standards suggest the presence of a yet uncharacterized T-cell mitogen.
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PMID:Mitogenic stimulation of human tumor-infiltrating lymphocytes by secreted factor(s) from human tumor cell lines. 219 Feb 13

The use of interleukin 2-based immunotherapies for cancer has been associated with significant responses in tumor models in both mouse and humans. Further definition of the elements responsible for response is now possible. It appears that the response is associated with T-cell infiltration of the tumor, and transfer of tumor-infiltrating lymphocytes expanded in tissue culture with interleukin 2 is associated with significant antitumor effects. Further expansion of cultured human melanoma tumor-infiltrating lymphocytes with suppression of lymphokine-activated killer activity as well as the modulation of monocyte activity by interleukin 4 suggests that this cytokine may be clinically useful alone or in combination with interleukin 2. Other means of enhancing the activity of interleukin 2-based immunotherapy are suggested by the finding that tumor cell susceptibility to lysis by natural killer cells is depressed following treatment with interferon gamma and tumor necrosis factor, but susceptibility to lysis by tumor-infiltrating lymphocytes is markedly enhanced. Further development of these therapies will require innovative interpretation and application of findings related to the processing and presentation of human tumor antigens and the nature of tumor antigens and careful analysis of the T-cell receptor in antitumor effectors.
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PMID:Mechanisms of immunologic antitumor therapy: lessons from the laboratory and clinical applications. 219 Sep 52

In vitro, the combination of interleukin-2 (Il-2) with interferon-alpha (IFN-alpha) seems to act synergistically on the generation of lymphokine activated killer (LAK) cells. Due to this fact two clinical trials with the combination of Il-2 and IFN-alpha were initiated in malignant melanoma (MM) and renal cell cancer (RCC). Patients with disseminated MM were treated by a sequential application of 10 x 10(6) U/m2 rIFN-alpha 2b s.c. on days 1-7 followed by continuous intravenous infusion of 3 x 10(6) U/m2 rIl-2 on days 8-13 and 15-20. After a pause of 4 weeks the cycle was repeated. In advanced or disseminated RCC, the patients were treated with a daily alternating scheme of 10 x 10(6) U/m2 rIFN-alpha and rIl-2 as 1 h infusion 1 x /day for 14 days. The rIl-2 escalates intra- and interindividually beginning with a dose of 3 x 10(6) U/m2. The cycles were repeated after a pause of 3 and 4 weeks, respectively. The preliminary results show that the schedules are practicable and that the toxicity of the combination of rIl-2 and IFN-alpha does not accumulate. Within the MM group 3/11 evaluable patients achieved partial remission and 2/11 stable disease. In the RCC-group 2/5 evaluable patients achieved partial remission and 2/5 had stable disease so far.
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PMID:Interleukin-2 in combination with interferon-alpha in disseminated malignant melanoma and advanced renal cell carcinoma. A phase I/II study. 219 85


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