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 V gamma 5/V delta 1(+)-T-cell receptor (TCR)-bearing T-cell clone, 2CBET-3, was generated from C57BL/6 mice. Upon stimulation, 2CBET-3 cells produce interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha, but not IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, macrophage colony-stimulating factor, or interferon-gamma. These cells were evaluated for their ability to be stimulated by a variety of murine cell lines, including fibroblasts, trophoblasts, melanoma cells, embryonic carcinomas, B-cell lymphomas, mastocytoma cells, and keratinocytes. The human B-lymphoma cell line, Daudi, also was included in these studies. We found that 2CBET-3 cells produced cytokines up to several hundredfold above the control levels in response to the B-cell lines, Daudi, and A20/2J, but not to the B-cell line 439.4.2. After fixation with glutaraldehyde, Daudi and A20/2J continued to stimulate this gamma delta T-cell line. 2CBET-3 cells also responded to the keratinocyte line PAM212, but not to another, XB-2. When lipopolysaccharides (LPS) from Escherichia coli or S. typhimurium were added to 2CBET-3 cells in the presence of A20/2J cells, 2CBET-3 cells responded with increased cytokine production compared with the cytokine production in the presence of A20/2J cells alone. 2CBET-3 cells by themselves did not respond to LPS alone or to supernatants from A20/2J cells incubated with LPS. Unlike 2CBET-3, the epidermal T-cell hybridoma 70BET-49, expressing a V gamma 5/V delta 1-TCR identical to that of 2CBET-3, did not respond to A20/2J cells in the presence or absence of LPS, suggesting a requirement for molecules other than the TCR for V gamma 5/V delta 1-TCR+ T-cell stimulation by the B-cell lines and by LPS. This unique reactivity of gamma delta-TCR+ cells is different from that of alpha beta-TCR+ cells and may reflect a functional specialization of gamma delta-TCR+ cells in the response to bacterial infections.
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PMID:Murine epidermal V gamma 5/V delta 1-T-cell receptor+ T cells respond to B-cell lines and lipopolysaccharides. 761 98

Natural killer (NK) cells that infiltrated into the primary tumour site at an early stage of tumour development, were examined for their participation in the generation of anti-tumour cytotoxic T lymphocytes (CTL). NK cells, which were detected by anti-NK1.1 monoclonal antibody (mAb), increased in the peritoneal exudate cells (PEC) on days 3 and 7 after an intraperitoneal (i.p.) inoculation of syngeneic B16 melanoma cells. These tumour-infiltrating NK cells showed a high level of cytotoxic activity against NK-sensitive YAC-1 cells and an increased expression of interferon-gamma (IFN-gamma) mRNA and interleukin-2 (IL-2) mRNA. The in vivo depletion of NK cells with anti-NK1.1 mAb, prior to i.p. inoculation of B16 melanoma cells, resulted in an increased number of tumour cells in the PEC compared to NK cell non-depleted mice. Interestingly, the differences in tumour cell number between both groups were more prominent on days 7 and 14 than on day 3, which strongly suggested that early-infiltrating NK cells have a large influence on the subsequent anti-tumour response. The in vivo depletion of NK cells prior to immunization with melanoma cells abrogated the capacity of the spleen cells to generate CD8+ tumour-specific CTL after in vitro restimulation. This inability of generating anti-tumour CTL was partially restored by additional i.p. injections of recombinant IL-2 and/or IFN-gamma simultaneously with the immunization of melanoma cells. The in vitro depletion of NK cells prior to the in vitro restimulation with melanoma cells partially impaired the anti-tumour CTL generation from the spleen cells of the immunized mice. Lastly, the in vivo depletion of NK cells prior to immunization with melanoma cells abolished the protective immunity against melanoma cells at the rechallenge. Overall, these results indicate that early-appearing tumour-infiltrating NK cells not only participate in the anti-tumour early defence by themselves, but also play a crucial role in the generation of anti-tumour CTL.
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PMID:Early-appearing tumour-infiltrating natural killer cells play a crucial role in the generation of anti-tumour T lymphocytes. 764 26

In an effort to enhance the antigenicity of canine tumor cells, canine interferon-gamma (CnIFN-gamma) was applied in vitro to seven canine mammary tumor (CMT) and two canine melanoma (CML) cell lines. Surface expression of major histocompatibility complex (MHC) antigens and tumor-associated antigens (TAA) was measured by a flow cytometric fluorescence assay using commercially available anti-MHC antibodies, and anti-canine TAA monoclonal antibodies generated against CMT and CML cell lines. Compared to constitutive antigen levels in untreated cells, treatment with CnIFN-gamma resulted in increased expression of MHC class I and II antigens (up to 19- and 167-fold, respectively) and a TAA (up to 5-fold) by CMT cell lines, and increased expression of class I antigen (131-fold) by one CML and of class II antigen (18-fold) by the other CML cell line. Expression of MHC antigens and a TAA by tumor cells was increased by Cn-IFN-gamma treatment, and such an increase may be of potential benefit in tumor cell recognition and rejection by the immune system.
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PMID:Modulation by canine interferon-gamma of major histocompatibility complex and tumor-associated antigen expression in canine mammary tumor and melanoma cell lines. 764 83

The response of mouse T cells to the superantigen staphylococcal enterotoxin A (SEA) requires 1000-fold higher concentrations compared to human T cells. In order to develop a sensitive model for SEA studies in mice, the immunopharmacology has been studied in T-cell receptor (TcR) V beta 3 transgenic (TGV beta 3) and non-transgenic (non-TG) C57Bl/6 mice. The frequency of SEA-responsive T cells in the TGV beta 3 mice exceeded 90%, whereas a 10-fold lower frequency was seen in normal C57Bl/6 mice. Nanograms of SEA injected intravenously into TGV beta 3 mice induced strong cytolytic T lymphocyte (CTL) activity against SEA-coated major histocompatibility complex (MHC) class II+ B-lymphoma cells, whereas administration of 1000-fold higher amounts of SEA to non-TG littermates or normal C57Bl/6 mice induced only a moderate response. Kinetic analysis demonstrated that the CTL activity was more rapidly detectable in TG mice, but substantial levels were seen 2 days after SEA injection in both TGV beta 3 and non-TG mice. The cytotoxic T-cell response induced by SEA in TGV beta 3 and non-TG mice was completely MHC class II dependent, as SEA-coated MHC class II-transfected syngeneic B16 melanoma cells but not untransfected B16 cells were sensitive to lysis. Large amounts of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) accumulated in serum of TGV beta 3 mice after injection of 10 ng SEA, whereas only marginal amounts were recorded in non-TG even after injection of 100 micrograms SEA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that SEA-induced TNF-alpha and IFN-gamma mRNA reached maximal levels 1 hr after SEA administration in TGV beta 3 mice, whereas peak serum levels of TNF-alpha and IFN-gamma proteins were recorded after 2 hr. Comparison of the mRNA levels of a panel of cytokines in the TGV beta 3 and non-TG mice revealed that almost similar amounts of interleukin-1 (IL-1) were induced in both strains, whereas IL-4 was only detected at significant levels in the TGV beta 3 mouse. The results suggest that TGV beta 3 mice are suitable for studying in vivo immune responses to superantigens at concentrations comparable to the potent effects elicited in humans. Moreover, this model is useful for detailed studies on the dynamic regulation of T-cell activation and anergy induced by superantigens.
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PMID:Immunopharmacology of the superantigen staphylococcal enterotoxin A in T-cell receptor V beta 3 transgenic mice. 769 31

The growth of a potentially antigenic tumor in an immunocompetent host is taken as an indication that the malignant cells 'escaped' the cytotoxic capacity of the immune system. An increase in our knowledge of the means by which antigens are processed and expressed allows a greater understanding of the mechanism that enables tumor cells to avoid host immunity. It provides a rationale for new, more innovative forms of treatment. Antigenic determinants are presented to cytotoxic T lymphocytes (CTLs) in the context of class I determinants, structures specified by genes within the major histocompatibility complex. Potentially antigenic tumors may express lower levels of class I determinants than surrounding non-neoplastic cells. As a consequence, the tumor-associated T cell epitopes formed by the malignant cells may go unrecognized by tumor-specific CTLs. The introduction of genes specifying class I determinants into low class I expressing tumor cells increased class I expression and restored the cells' immunogenic properties. Treatment of low class I expressing cells with interferon-gamma, or the introduction of the interferon-gamma gene into the cells resulted in an increase in the expression of class I determinants as well, and, as a consequence, recognition of the malignant cells by the immune system. Nevertheless, an immunotherapeutic strategy that stimulated a single anti-tumor effector mechanism might be unable to eliminate a heterogeneous tumor cell population. To investigate this point, mice with melanoma were treated with a mixture of interferon-gamma-secreting and IL-2-secreting cellular immunogens. The animals survived significantly longer than mice with melanoma treated with either the IL-2 or interferon-gamma-secreting immunogens alone. The complexity of the problem was illustrated by the fact that although survival was prolonged, tumor growth recurred in each instance.
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PMID:Neoplastic cells that express low levels of MHC class I determinants escape host immunity. 770 41

Adequate wide excision of a primary cutaneous melanoma is associated with a 10-year cure rate of 85% when the tumor's depth is less than 1.5 mm (American Joint Committee on Cancer [AJCC] Stage I). However, 50% of patients with deep (> 4 mm) primary melanomas, 60-85% of those with regional lymph node metastases (AJCC Stage III), and 95% of those with metastases to distant sites (AJCC Stage IV) will experience recurrence, which is associated with a dismal prognosis. Adjuvant therapy of melanoma assumes that treatment will be more effective when the tumor burden is small. In the 1970s and 1980s, randomized trials tested the efficacy of chemotherapy, nonspecific immunotherapy, levamisole, and regional perfusion therapy in patients with AJCC Stage II and III melanoma. Dacarbazine (DTIC) alone or in combination with other chemotherapeutic drugs or with nonspecific immunotherapy did not significantly improve disease free or overall survival. Of the four levamisole trials, only the study conducted by the National Cancer Institute of Canada revealed a reduction in recurrence and mortality; however, this reduction was not significant by multivariate analysis. The value of regional perfusion therapy following resection of high risk extremity melanomas is currently being determined by multiinstitutional studies conducted by the World Health Organization and the North American Perfusion Group. Multi-institutional trials also are examining the adjuvant role of interferon-alpha in patients with deep (> 3 mm) primary melanomas or positive regional lymph nodes; results should reveal its optimum dose and duration of treatment (3 x 10(6) U for > or = 2 years versus 10 x 10(6) U/m2 for 1 year, subcutaneously 3 times a week) and its impact on survival. A randomized trial of interferon-gamma undertaken by the Southwest Oncology Group was discontinued after interim analysis indicated an adverse effect. Phase II trials indicate that active specific immunotherapy can alter the natural course of AJCC Stage III and IV melanoma following surgical resection of nodal or distant metastases. Upcoming results of Phase III trials will establish the role of active specific immunotherapy for adjuvant treatment of patients with resected AJCC Stage III and IV melanoma.
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PMID:The role of adjuvant therapy in melanoma management. 780 1

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
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PMID:Rationale for using TNF alpha and chemotherapy in regional therapy of melanoma. 780 92

Human peripheral blood monocytes derived from normal donors, melanoma patients (MP) before and after chemotherapy (MPa) were assayed for their capacity to inhibit SK-MEL-28 melanoma cell growth in vitro; in addition, growth modulating effects by prothymosin alpha 1 (ProTa) were studied. After preincubation with or without ProTa for 1 day, monocytes were cultured in the absence or presence of interferon-gamma (rIFN-gamma) for a further day, and after cocultivation with SK-MEL-28 melanoma cells for 3 days monocyte/macrophage-mediated tumoristatic activity was determined employing the microculture tetrazolium (MTT) assay. The level of baseline growth inhibitory activity of unstimulated MP and MPa monocytes was 22% and 15%, respectively, and was significantly lower (p < 0.001) than that of normal monocytes (35%). The stimulation of monocytes/macrophages by rIFN-gamma greatly elevated the mean of their antitumor activity up to 44%, 49% and 58% in the group of MP, MPa and normal donors, respectively. ProTa significantly increased the level of monocyte-mediated growth inhibition of MP and normal donors, when it was applied alone or in combination with rIFN-gamma. Monocytes of MP at early stages (I and II) of their disease, when incubated with rIFN-gamma, showed a higher increase in tumoristatic activity than at stage III and tended to be the most susceptible to preincubation with ProTa followed by rIFN-gamma activation. However, on average tumoristatic activity of MP/MPa monocytes was significantly lower compared with that of normal monocytes, when activated with rIFN-gamma or ProTa alone or combined. Moreover, no effects on TNF-alpha secretion of MP/MPa monocytes were found by ProTa and/or rIFN-gamma, whereas TNF-alpha levels from normal monocytes were significantly increased by the two stimuli. These results indicate that monocyte disorders in melanoma patients may be partially normalized by ProTa.
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PMID:Prothymosin alpha augments deficient antitumor activity of monocytes from melanoma patients in vitro. 787 60

Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response compared with 52% after ILP with melphalan alone. Leakage and release of nanograms levels of TNF alpha in the systemic circulation can be abrogated in most patients by low pump flow, continuous leak monitoring, extensive washout, and limb massage. In case of unavoidable leakage, appropriate intensive care results in minimal toxicity. The ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in humans.
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PMID:Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of advanced melanoma. 789 25

Interleukin-12 (IL-12) is a B-cell and monocyte-derived 75 kDa heterodimeric cytokine released early after immune stimulation. It promotes the cytolytic maturation and proliferation of T and natural killer (NK) cells and release of interferon-gamma from these effectors. Furthermore, IL-12 appears to stimulate the production of a Th1 immune response. We have examined the effects of IL-12 on the proliferation and lytic activity of fresh peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs). IL-12 stimulates proliferation of PBMCs by as much as 10-fold after T-cell receptor (TCR) ligation induced by anti-CD3 or phytohemagglutinin. In contrast, IL-12 promotes only marginal proliferation of resting PBMCs. IL-12 modulates IL-2-induced lymphokine-activated killer (LAK) cell activity: it inhibits IL-2 LAK when added early to culture but augments LAK activity in PBMCs preactivated by IL-12. IL-12 induces the proliferation (three- to fourfold above background) and enhances the cytolytic activity (two- to fourfold) of TIL lines and melanoma-derived, peptide-specific T-cell clones that have been recently restimulated with autologous tumor. These results suggest that IL-12 may serve in vivo to amplify and focus the cellular immune response by selectively inducing the outgrowth and enhancing the lytic potential of T and NK cells that have received the proper coactivation signals.
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PMID:Interleukin-12 promotes the proliferation and cytolytic maturation of immune effectors: implications for the immunotherapy of cancer. 790 80


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