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)

Recombinant immune interferon (IFN-gamma) induced a dose-related increase in the synthesis and expression of HLA class II antigens by the cultured melanoma cells COLO 38. Although IFN-gamma-treated melanoma cells COLO 38 continue to express higher levels of HLA-DR antigens than of HLA-DQ antigens, the effect of IFN-gamma was more marked on HLA-DQ antigens than on HLA-DR antigens, as indicated by the dose and incubation time required to induce the changes and by the extent and duration of the increase. The effect of IFN-gamma on HLA class II antigens is significantly higher than that of leukocyte and fibroblast interferons. Analysis by one- and two-dimensional gel electrophoresis of antigens synthesized by melanoma cells COLO 38 in the presence of IFN-gamma did not detect any significant change in the structural profile of the subunits of HLA-DR and -DQ antigens.
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PMID:Differential susceptibility to modulation by recombinant immune interferon of HLA-DR and -DQ antigens synthesized by melanoma COLO 38 cells. 310 Apr 20

The effect of recombinant immune interferon (IFN-gamma) on the expression and shedding of HLA antigens and of melanoma-associated antigens (MAA) by epidermal melanocytes was investigated by using serologic and immunochemical techniques. IFN-gamma enhances the expression and/or shedding of HLA class I antigens and of the cytoplasmic MAA defined by monoclonal antibody (MoAb) 465.12S and induces a slight reduction in the expression of the high m.w. melanoma-associated antigen (HMW-MAA). In agreement with the data in the literature, melanocytes incubated with IFN-gamma acquire HLA-DR, -DQ, and -DP antigens. Contrary to previous information in the literature, the effect is not restricted to HLA class II antigens, since IFN-gamma also induces the expression of the 96-kDa MAA recognized by MoAb CL203. The effect of IFN-gamma on HLA class II antigens and 96-kDa MAA is dose and time dependent and is specific, because recombinant leukocyte interferon affects the expression of neither type of antigen. In spite of the expression of HLA class II antigens, IFN-gamma-treated melanocytes do not acquire the ability to stimulate the proliferation of allogeneic lymphocytes. HLA-DR antigens are more susceptible to induction by IFN-gamma than HLA-DQ and -DP antigens, since the percentage of melanocytes acquiring HLA-DQ and -DP antigens is lower than that acquiring HLA-DR antigens. Furthermore, the dose of IFN-gamma is higher and the time of incubation is longer to induce HLA-DQ and -DP antigens than to induce HLA-DR antigens. The differential susceptibility of HLA-DR, -DQ, and -DP antigens as well as of melanocytes from various donors to the modulating effect of IFN-gamma may provide an explanation for the more frequent detection of HLA-DR than of HLA-DQ and -DP antigens in melanoma lesions and for the expression of HLA class II antigens by some, but not all, melanoma lesions.
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PMID:Immunochemical and functional analysis of HLA class II antigens induced by recombinant immune interferon on normal epidermal melanocytes. 310 Jun 35

To develop monoclonal antibodies (mAb) recognizing human melanoma-associated antigens (MAA) susceptible to modulation by immune interferon (IFN-gamma), hybridomas were constructed with splenocytes from a BALB/c mouse immunized with IFN-gamma-treated melanoma cells Colo 38. Screening of supernatants with control and IFN-gamma-treated melanoma cells showed that the mAb CL203 and CL207 display preferential reactivity with IFN-gamma-treated melanoma cells. The two mAb recognize the same (or spatially close) determinant on a 96,000 MAA which has a density of 0.36 X 10(6) antigenic sites/cell on untreated melanoma cells Colo 38 and of 1.39 X 10(6) and 1.54 X 10(6) on melanoma cells Colo 38 treated with IFN-gamma (final concentration, 200 U/ml) for 24 and 48 hr, respectively. The effect of IFN-gamma on the 96,000 MAA is dose- and time-dependent, reversible, and blocked by inhibitors of RNA and protein synthesis. Furthermore, the effect of IFN-gamma on the induction of the 96,000 MAA appears to be specific, inasmuch as IFN-alpha and IFN-beta do not induce the expression of the 96,000 MAA. The latter is also induced by IFN-gamma in a variety of carcinoma cell lines, but its level is markedly lower than on melanoma cells. Furthermore, the apparent m.w. of the antigen synthesized by the carcinoma cell lines in the presence of IFN-gamma ranges between 93,000 and 96,000. This molecular heterogeneity appears to reflect differences in the degree of glycosylation of the polypeptide moiety because the antigen synthesized by a variety of cell lines in the presence of tunicamycin has an apparent m.w. of 51,000.
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PMID:Characterization of a monoclonal antibody-defined human melanoma-associated antigen susceptible to induction by immune interferon. 311 85

Between 1-1-85 and 6-30-86, 17 patients suffering from metastatic malignant melanoma received total doses of 30-40 I.U. IFN-gamma given i.v. in a daily fractionation of 1.0-2.6 X 10(6) I.U. The only side effect was fever grade I-II (WHO). In four of these patients a regression of the disease was obtained (two complete remissions and two partial remissions, according to UICC criteria). Thus, the overall response rate was 23.5%. The average duration of remission was 8.9 months (range from 1.5 to 21 + months), the average survival time 12.4 months (range from 1.5 to 21 + months, also). Two other patients showed no change lasting for two and five months respectively. In all, systemic interferon-gamma treatment applied in the manner described seems to be able to induce remissions in single cases without showing severe toxicity.
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PMID:Interferon-gamma treatment of metastasized malignant melanoma. 311 73

The relationship between major histocompatibility complex (MHC) antigens and metastasis was investigated on B16 melanoma variants. B16 cell lines express low amounts of murine MHC (H-2) antigens. A high expression can be induced in line B16-A by in vitro treatment with immune interferon (IFN-gamma) or by in vivo transplant in allogeneic mice. The increase of H-2 antigens correlated with an enhancement of lung colonization in young syngeneic mice. The higher metastatic capacity of B16-A cells with induced high levels of H-2 antigens was observed also in adult mice and in young mice pretreated with cyclophosphamide. These results were confirmed investigating the behaviour of a mutant B16 clone (B78H1) which was selectively resistant to the H-2-inducing action of IFN-gamma: lung colonization ability was not increased by IFN pretreatment. The study of variants derived from individual B16-A lung colonies revealed a wide range of H-2 levels. Variants with a low expression had a low colonization ability; one out of two variants with a high H-2 expression also was poorly colonizing. IFN-gamma-mediated H-2 expression appeared to act as an enhancer, rather than a determinant of B16 metastatic capacity.
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PMID:Interferon-mediated enhancement of metastasis. Are MHC antigens involved? 311 68

Successful immunotherapy of early s.c. or i.p. (B16) melanoma in syngeneic C57BL/6 (B6) mice was achieved with s.c. peri-lesional injections (for s.c. tumors) or i.p. injections (for i.p. tumors) of recombinant human interleukin 2 (rIL-2) and recombinant murine interferon-gamma (rIFN-gamma). Over a 28-day period, rIL-2 and rIFN-gamma were injected 14 times. Results with this combination were additive with s.c. tumors and synergistic with i.p. tumors. Treatment with 6,250 U-25,000 U of rIL-2 and 2 micrograms of rIFN-gamma began 1-3 days after s.c. inoculation of melanoma. On day 50, 87% (72/83) of mice thus treated were completely free of tumor. None of the 78 control mice (tumor + buffer) survived. Of mice receiving either rIL-2 or rIFN-gamma alone, 59% (47/79) and 53% (44/83), respectively, were tumor-free. I.p. tumors were also eradicated by i.p. injections of rIL-2 (50,000 U) with rIFN-gamma (5, 10, and 15 micrograms) as judged by absence of tumor in 81% (21/26) of mice autopsied between days 45 and 65. No control mice survived, and only 17% (2/12) and 20% (6/30) given either rIL-2 or rIFN-gamma separately (i.p.) were tumor-free. Doses of rIFN-gamma from 1-4 micrograms were more beneficial in eliminating 1-day s.c. melanomas than were higher doses, and local s.c. treatment was far superior to distant or systemic treatment. Non-adherent peritoneal or splenic cells from mice bearing 6-day-old i.p. melanomas and treated with one or both lymphokines on days 3 and 4 were used in cytotoxicity assays in vitro. Significant cytotoxicity against cultured melanoma cells was displayed by cells harvested from lymphokine-treated mice, but there was no evidence of the synergism observed with combination treatment of i.p. tumors in vivo. rIFN-gamma inhibited proliferation of melanoma cells in vitro, whereas rIL-2 stimulated proliferation at 1,000 U/ml. Plating efficiency was increased by at least 30% by culture with 100 U or 1,000 U of rIL-2/ml and both concentrations neutralized the inhibitory effect of 0.05 ng/ml of IFN-gamma, but not of 0.5 or 5.0 ng/ml.
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PMID:Eradication of mouse melanoma by combined treatment with recombinant human interleukin 2 and recombinant murine interferon-gamma. 312 4

IFN-gamma increases the synthesis and level of mRNA of the HLA class I and II genes, in human cells such as melanomas which normally express both classes of molecules. It also induces the surface expression and mRNA synthesis of HLA-DR genes on cells which normally do not express HLA class II genes such as skin fibroblasts. We have investigated the mechanism by which IFN-gamma increases mRNA levels for class II MHC antigens in human cells. For this purpose, we have studied the effect of IFN-gamma on HLA-DR-alpha transcription rate in two different human cell types: VAL melanoma and JDA2 skin fibroblasts. HLA-DR-alpha mRNA is spontaneously produced in VAL cells and its level is enhanced upon IFN-gamma treatment. We demonstrate here that IFN-gamma increases the transcription of HLA-DR-alpha gene in this cell line. However, the discrepancy observed between HLA-DR-alpha mRNA and transcriptional rates led us to postulate that IFN-gamma also regulates the HLA-DR-alpha gene post-transcriptionally. In the course of these experiments, we found also that human skin fibroblasts, which do not contain detectable amounts of HLA-DR-alpha mRNA, spontaneously transcribe the HLA-DR-alpha gene.
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PMID:Regulation of HLA-DR gene by IFN-gamma. Transcriptional and post-transcriptional control. 312 33

Progression of human melanoma is associated with changes in antigenic phenotypes of tumor cells. To establish whether inflammatory infiltrates in progressing melanoma also change, we studied 146 cutaneous melanomas at different stages of progression. Monoclonal antibodies (MAbs) against lymphocyte and macrophage subpopulations, interleukin-2 receptor (IL-2 R), immune interferon (IFN-gamma), and the IFN-gamma-inducible, progression-associated melanoma antigens HLA-DR and gp89 were applied in situ. During the course of melanoma progression, decreased amounts of peritumoral T cells, IL-2 R-expressing lymphocytes and dermal T6+ dendritic cells were found, while increased numbers of intratumoral T cells, inflammatory (27E10+) and mature (25F9+) macrophages were associated with local progression of primary melanomas. In metastases, most infiltrate components except 25F9+ macrophages were rare. Positive correlations were observed between: (1) dermal T6+ cells and IL-2 R+ lymphocytes, and (2) presence of IFN-gamma in the infiltrate and HLA-DR and gp89 antigens on tumor cells. In all stages, HLA-DR expression on tumor cells was correlated with: (1) a shift towards T8+ lymphocytes in the infiltrates and (2) a loss of IL-2 R expression. Our data suggest mutual influences between melanoma cells and mononuclear cell infiltrates in situ.
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PMID:Inflammatory cell infiltrates in human melanoma at different stages of tumor progression. 312 89

Despite quantitative as well as qualitative differences, all three types of IFN (IFN-alpha, IFN-beta, and IFN-gamma) modulate the synthesis as well as the expression of class I and class II histocompatibility Ag and a melanoma-associated Ag located in the plasma membrane as well as the cytoplasm of human melanoma cells. By employing inhibitors of RNA and protein synthesis it was demonstrated that IFN-alpha and -beta increase the expression of histocompatibility products and this tumor-associated Ag by a process not requiring new protein synthesis. In contrast, IFN-gamma does require de novo protein synthesis for its modulatory activity. Thus, it appears that IFN might trigger various adaptive functions in different cell lineages by inducing at least two separate sets of responses specific for either IFN-alpha and -beta or IFN-gamma. Because the induction requirements for (2'-5')-oligoadenylate synthetase as well as for the development of a cellular antiviral state by different IFN also display a similar protein synthesis dependence pattern, the present results suggest that a similar set of cellular mediators may be involved in the modulation of antigenic expression by IFN-gamma in human melanoma cells.
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PMID:Recombinant human IFN-gamma, but not IFN-alpha or IFN-beta, enhances MHC- and non-MHC-encoded glycoproteins by a protein synthesis-dependent mechanism. 312 9

The mechanism of therapeutic activity of recombinant murine interferon-gamma (rMu IFN-gamma) and the IFN inducer polyinosinic-polycytidylic acid solubilized with poly-L-lysine in carboxy methyl cellulose (pICLC) in treating metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the organ with tumor) were tested after 1 and 3 weeks of rMu IFN-gamma or pICLC administration (intravenous, three times a week). In these studies, natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocytes (CTL) (against specific and nonspecific targets), and macrophage tumoricidal and tumoristatic activities were measured. rM IFN-gamma and pICLC had therapeutic activity and immunomodulatory activity in most assays of immune function examined. Specific CTL activity of pulmonary parenchymal mononuclear cells (PPMC), but not in splenocytes or peripheral blood lymphocytes (PBL), during week 3 and not during week 1, correlated with the therapeutic activity of rMu IFN-gamma and of pICLC. Macrophage tumoricidal activity in PPMC, but not in alveolar macrophages, also correlated with the therapeutic activity of rMu IFN-gamma, but the opposite was true for the therapeutic activity of pICLC. NK activity of PPMC, but not of splenocytes or PBL, during week 1 correlated with the therapeutic activity of pICLC; in contrast, NK activity at any site did not correlate with the therapeutic activity of rMu IFN-gamma. LAK activity at any site did not correlate with the therapeutic activity of either agent.
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PMID:Correlation of immunomodulatory and therapeutic activities of interferon and interferon inducers in metastatic disease. 313 67


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