Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical experience that spontaneous anti-melanoma immune reactivity can occur has stimulated the search for methods to induce this in patients diagnosed with melanoma. Non-specific approaches using a variety of immune stimulants such as BCG or cytokines have met with limited success, as have vaccines derived from tumour cells. More recently, melanoma antigens have been identified that can act as specific targets for immune recognition. Cell surface glycolipids such as the gangliosides GM2 and GD3, can be targeted by antibodies. This has provided the basis for clinical trials with ganglioside vaccines and monoclonal antibody infusions. Antigens recognized by cytotoxic lymphocytes have also been described in the last 5 years. These are peptide antigens derived from intracellular proteins which are present on the cell surface in association with HLA molecules. These antigens include MAGE 1 and 3, tyrosinase, MelanA/MART-1 and gp100. Clinical trials with these have commenced and novel treatment strategies are being developed. Since tumours can be typed for specific antigens and specific immune responses can be measured, the reasons for treatment success or failure can be analysed more effectively than in the past. For example, the emergence of antigen-negative tumour variants can be assessed. This should enable a more systematic approach for developing new immunotherapies for melanoma.
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PMID:Immunotherapy of melanoma: targeting defined antigens. 1099 77

A total of 17 patients with metastatic melanoma were treated with intratumoral interferon-gamma (IFN-gamma) retroviral vector in a phase I clinical trial. A cycle of treatment consisted of five daily injections every 2 weeks. Patients were divided into two treatment arms that involved a single course (one cycle) of treatment (group I; n = 9) and multiple cycles (six cycles) of treatment (group II; n = 8). Patients received intratumoral injections of IFN-gamma (10(7) plaque-forming units/mL administered at 0.3, 0.5, and 1.0 mL per cohort of patients). All patients receiving multiple injections either maintained stable disease (n = 5) or achieved a partial or complete response (n = 3) of the injected lesion, whereas in patients receiving a single cycle of treatment, only one of nine patients had a response. Patients were assessed for immunoglobulin G antibody (Ab) responses to the melanoma-associated antigens (MAA) tyrosinase, gp100, TRP-2, and MAGE-A1 by affinity enzyme-linked immunosorbent assay. Anti-MAGE-A1 and tyrosinase Ab were significantly elevated from baseline (day 0) to week 16 during treatment (P = .005; P = .002, respectively) in patients who received multiple injections. Patients undergoing treatment who had a clinical response (stable disease or better) also had significantly more elevated Ab responses to a greater number of MAA (P = .0004). The induction of systemic Ab responses to multiple MAA also correlated with systemic clinical responses. These studies suggest that multiple anti-MAA Ab responses are associated with clinical responses to IFN-gamma retroviral treatment and may be used as surrogate response markers.
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PMID:Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-gamma retroviral vector in melanoma patients. 1102 94

Dendritic cells (DCs) elicit potent anti-tumoral T-cell responses in vitro and in vivo. However, different types of DC have yet to be compared for their capacity to induce anti-tumor responses in vivo at different developmental stages. Herein, we correlated the efficiencies of different types of monocyte-derived DC as vaccines on the resulting anti-tumor immune responses in vivo. Immature and mature DCs were separately pulsed with a peptide derived from tyrosinase, MelanA/MART-1 or MAGE-1 and a recall antigen. Both DC populations were injected every 2 weeks in different lymph nodes of the same patient. Immune responses were monitored before, during and after vaccination. Mature DCs induced increased recall antigen-specific CD4(+) T-cell responses in 7/8 patients, while immature DCs did so in only 3/8. Expansion of peptide-specific IFN-gamma-producing CD8(+) T cells was observed in 5/7 patients vaccinated with mature DCs but in only 1/7 using immature DCs. However, these functional data did not correlate with the tetramer staining. Herein, immature DCs also showed expansion of peptide-specific T cells. In 2/4 patients vaccinated with mature DCs, we observed induction of peptide-specific cytotoxic T cells, as monitored by chromium-release assays, whereas immature DCs failed to induce peptide-specific cytotoxic T cells in the same patients. Instead, FCS-cultured immature DCs induced FCS-specific IgE responses in 1 patient. Our data demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient. Thus, our data define FCS-free cultured mature DCs as superior inducers of T-cell responses in melanoma patients.
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PMID:A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. 1141 Aug 73

A majority of desmoplastic melanomas and some of the other forms of melanomas are S-100 positive and HMB45 negative; this pattern of immunoreactivity is similar to certain nerve-derived tumors such as malignant peripheral nerve sheath tumor. In this study the immunostaining profile of HMB45-negative malignant melanomas was evaluated by a panel of antibodies against markers associated with melanoma and melanocytic differentiation, including microphthalmia transcription factor, tyrosinase, Melan-A, and MAGE-1. Immunodetection was performed on paraffin sections of 22 cases of HMB45-negative malignant melanomas (including 8 spindle cell melanomas, 8 desmoplastic melanomas, and 6 epithelioid melanomas), 8 HMB45-and S-100-positive malignant melanomas, 15 malignant peripheral nerve sheath tumors, 16 schwannomas, and 11 neurofibromas. Of eight HMB45-positive malignant melanomas, all were positive for Melan-A, tyrosinase, and melanocyte-specific transcription factor, and three were positive for MAGE-1. In the 14 HMB-45 negative, nondesmoplastic melanomas, melanocyte-specific transcription factor was positive in 9, Melan-A in 9, tyrosinase in 6, and MAGE-1 in 11. In eight desmoplastic malignant melanomas, MAGE-1 was positive in three, and all other markers were negative. The five markers tested were negative in all but two schwannomas, one with focal melanocyte-specific transcription factor and the other with tyrosinase and weak MAGE-1 reactivity. MAGE-1, melanocyte-specific transcription factor, tyrosinase, and Melan-A are useful markers in the diagnosis of malignant melanocytic lesions when HMB45 is negative. MAGE-1 may be useful in differentiating melanocytic lesions from nerve-derived lesions, but its sensitivity is relatively low. The immunostaining profile of desmoplastic malignant melanomas more closely resembles that of malignant peripheral nerve sheath tumor than that of other types of malignant melanoma. Melanocyte-specific transcription factor is not a useful marker for desmoplastic melanoma.
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PMID:Immunoprofile of MITF, tyrosinase, melan-A, and MAGE-1 in HMB45-negative melanomas. 1175 73

Among a number of human tumor antigens identified using the serological analysis of recombinant cDNA expression libraries (SEREX), only MAGE-1, tyrosinase, and NY-ESO-1 have been reported to be immunogenic tumor antigens that have the potential to elicit both humoral and cellular immunity. In this study, we determined whether our SEREX-defined pancreatic cancer antigens could be recognized by CTL, and report that one SEREX-defined antigen, coactosin-like protein (CLP), encoded cellular epitopes recognized by HLA-A2-restricted and tumor-reactive CTL. Three CLP peptides at positions 15-24, 57-65, and 10-113 possessed the ability to induce HLA-A2-restricted and tumor-reactive CTL from the PBMC of cancer patients. Subsequently, humoral responses to these peptides were investigated. IgG antibodies specific to the CLP 15-24, 57-65, and 104-113 peptides were detected in sera from 12, 0, and 12 of 12 cancer patients tested, and were also found in 5, 0, and 0 of 9 healthy donors, respectively. IgE antibodies specific to these peptides were also detected in sera from certain cancer patients and healthy donors. Since peptide-specific IgE was detected, type-I allergy to these peptides was tested. Unexpectedly the CLP 57-65 peptide, to which IgE was found in only 2 healthy donors, but not the other two peptides, was found to elicit an immediate-type hypersensitivity in all 10 healthy volunteers tested. These results indicate that identical antigenic peptides can be recognized by both cellular and humoral immune systems to a tumor-associated antigen. The CLP 15-24 and 104-113 peptides might be appropriate vaccine candidates for peptide-based immunotherapy of HLA-A2(+) cancer patients.
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PMID:Cellular and humoral immune responses to a human pancreatic cancer antigen, coactosin-like protein, originally defined by the SEREX method. 1187 Jun 27

We previously described HLA-B35-restricted melanoma tumor-infiltrating lymphocyte responses to frequently expressed melanoma-associated Ags: tyrosinase, Melan-A/MART-1, gp100, MAGE-A3/MAGE-A6, and NY-ESO-1. Using clones derived from these TIL, we identified in this study the corresponding epitopes. We show that five of these epitopes are new and that melanoma cells naturally present all the six epitopes. Interestingly, five of these epitopes correspond to or encompass melanoma-associated Ag epitopes presented in other HLA contexts, such as A2, A1, B51, and Cw3. In particular, the HLA-B35-restricted Melan-A epitope is mimicked by the peptide 26-35, already known as the most immunodominant melanoma epitope in the HLA-A*0201 context. Because this peptide lacked adequate anchor amino acid residues for efficient binding to HLA-B35, modified peptides were designed. Two of these analogues were found to induce higher PBL- and tumor-infiltrating lymphocyte-specific responses than the parental peptide, suggesting that they could be more immunogenic in HLA-B*3501 melanoma patients. These data have important implications for the formulation of polypeptide-based vaccines as well as for the monitoring of melanoma-specific CTL response in HLA-B*3501 melanoma patients.
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PMID:Identification of five new HLA-B*3501-restricted epitopes derived from common melanoma-associated antigens, spontaneously recognized by tumor-infiltrating lymphocytes. 1463 46

Melanoma antigen-encoding gene (MAGE-1) has been introduced as a sensitive immunohistochemical marker to aid in the diagnosis of malignant melanomas, in particular, those that are HMB-45 negative. Our goal was to determine the consistency of positive staining in melanomas on the basis of the usefulness of MAGE-1 in comparison with tyrosinase and MART-1. We studied 56 malignant melanomas using immunohistochemical markers to MAGE-1, tyrosinase, MART-1, HMB-45, and S-100. Six of 17 HMB-45-negative cases were strongly positive for MAGE-1 (35%), while 9 of 39 HMB-45-positive cases were positive for MAGE-1 (23%), overall, 27% positivity (n = 56). Tyrosinase and MART-1 were both strongly positive in 42 of 56 cases (75%). Fifty-two of 56 cases were strongly positive for S-100 (93%). We found MAGE-1 to be less sensitive than described in other studies, and overall, not very helpful, especially as a predictor of aggressive behavior. Although MAGE-1 expression has been considered as a target for immunomodulation therapy, our findings do not indicate consistent expression of this epitope in a majority of melanomas. S-100 protein, tyrosinase, and MART-1 immunomarkers were more frequently positive in our melanoma cases and appear to constitute a useful panel of markers to aid in the diagnosis of metastatic malignant melanomas, especially in patients with an unknown primary.
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PMID:Is MAGE-1 expression in metastatic malignant melanomas really helpful? 1522 57

The lack of melanoma-associated antigen (MAA) expression has been associated with the reduced overall survival in melanoma patients. In order to investigate whether the MAA expression detected on cell cultures established from melanoma patients might relate to the overall survival in these patients, we screened primary cell cultures derived from 37 melanoma metastases for the expression of five known MAA: Melan-A, tyrosinase, gp-100, MAGE-1 and MAGE-3 by polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS). MAA expression detected by PCR was found at a high percentage in evaluated melanoma cell lines: 25 of 28 (89%) were positive for Melan-A, 22 of 28 (79%) were positive for tyrosinase, 26 of 28 (93%) were positive for gp-100, and 18 of 28 (64%) were positive for MAGE-3 expression. Using the FACS method the percentage of MAA-positive cell lines was much lower: 14 of 31 (45%) cell lines were positive for Melan-A, eight of 31 (26%) were positive for tyrosinase, 13 of 31 (42%) were positive for gp-100, six of 31 (19%) were positive for MAGE-1, and 14 of 31 (45%) were positive for MAGE-3 expression. Kaplan-Meier survival analysis demonstrated that the patients whose cell lines were positive for Melan-A expression by PCR had significantly longer overall survival time as Melan-A PCR-negative cases (P=0.0038). This could not be shown for any of the markers tested by FACS. Our results suggest that the expression of Melan-A/MART-1 in patient-derived cell cultures may help to identify a group of melanoma patients with prolonged survival.
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PMID:Expression of Melan-A/MART-1 in primary melanoma cell cultures has prognostic implication in metastatic melanoma patients. 1530 55

BACKGROUND: Metastatic, chemotherapy-resistant melanoma is an intractable cancer with a very poor prognosis. As to immunotherapy targeting metastatic melanoma, HLA-A2+ patients were mainly enrolled in the study in Western countries. However, HLA-A24+ melanoma patients-oriented immunotherapy has not been fully investigated. In the present study, we investigated the effect of dendritic cell (DC)-based immunotherapy on metastatic melanoma patients with HLA-A2 or A24 genotype. METHODS: Nine cases of metastatic melanoma were enrolled into a phase I study of monocyte-derived dendritic cell (DC)-based immunotherapy. HLA-genotype analysis revealed 4 cases of HLA-A*0201, 1 of A*0206 and 4 of A*2402. Enriched monocytes were obtained using OptiPreptrade mark from leukapheresis products, and then incubated with GM-CSF and IL-4 in a closed serum-free system. After pulsing with a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-2, MAGE-3 and MART-1 or MAGE-1) restricted to HLA-A2 or A24 and KLH, cells were cryopreserved until used. Finally, thawed DCs were washed and injected subcutaneously (s.c.) into the inguinal region in a dose-escalation manner. RESULTS: The mean percentage of DCs rated as lin-HLA-DR+ in melanoma patients was 46.4 +/- 15.6 %. Most of DCs expressed high level of co-stimulatory molecules and type1 phenotype (CD11c+HLA-DR+), while a moderate number of mature DCs with CD83 and CCR7 positive were contained in DC products. DC injections were well tolerated except for transient liver dysfunction (elevation of transaminases, Grade I-II). All 6 evaluable cases except for early PD showed positive immunological responses to more than 2 melanoma peptides in an ELISPOT assay. Two representative responders demonstrated strong HLA-class I protein expression in the tumor and very high scores of ELISPOT that might correlate to the regression of metastatic tumors. Clinical response through DC injections was as follows : 1CR, 1 PR, 1SD and 6 PD. All 59 DC injections in the phase I study were tolerable in terms of safety, however, the maximal tolerable dose of DCs was not determined. CONCLUSIONS: These results suggested that peptide cocktail-treated DC-based immunotherapy had the potential for utilizing as one of therapeutic tools against metastatic melanoma in Japan.
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PMID:Clinical response in Japanese metastatic melanoma patients treated with peptide cocktail-pulsed dendritic cells. 1567 80

The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA - Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 - by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2. Melan-A, tyrosinase and gp100 expression was frequently reduced in melanoma cell cultures, compared to that in foreskin melanocytes, whereas MAGE-1 and MAGE-3 expression showed variable degree of upregulation, compared to that in foreskin melanocytes. The expression of all tested MAA demonstrated high interindividual variability. We further show that cell cultures derived from the same tissue sample are oligoclonal in nature, by demonstrating the presence of up to three cell populations bearing distinct MAA profile. Analysing samples derived from the same patient but each at a different time point, we show that MAA expression profile changes over time either in positive (increase) or in negative (decrease) direction. Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P-value range: 0.05-0.001). Elucidation of the MAA expression patterns and the kinetics within the same patient as well as during the course of the disease may help improve current and develop new immunotherapeutic strategies.
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PMID:Expression of melanoma-associated antigens in melanoma cell cultures. 1594 36


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