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)

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27-81), with performance status 0-2 were treated with merbarone 1000 mg/m2/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-responders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%-19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%0, malaise (23%), weakness (20%), alopecia (17%), diarrhea (17), anorexia (14%) transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5'nucleotidase increase (9%), and fever (9%). Hematologic toxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.
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PMID:Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma. A Southwest Oncology Group study. 861 77

Sixty-five patients with advanced melanoma treated in phase II trials with interferon-alpha and high dose interleukin-2 were analysed for pretreatment prognostic parameters. Three levels of response were used: objective remission [three complete response (CR)/14 partial response (PR)], stable disease and progression. Elevated lactate dehydrogenase (LDH), impaired performance status and high tumor load were associated with poor response. Multivariate analysis considering two levels of response [CR/PR vs stable disease (SD)/progressive disease (PD)] did not reveal any model with more than one significant factor. Considering survival, LDH was also a strong factor. Additional prognostic factors here were performance status, metastatic sites, alkaline phosphatase and tumor load. A Cox regression analysis revealed LDH, performance status and metastatic sites as independent factors. The prognostic values of these parameters will have to be confirmed in a larger patient cohort. Using the landmark method, it was estimated whether the response obtained after two cycles of treatment predicted survival. Patients with PD at this time had a median further survival of 6 months, SD of 27 months, and PR/CR of more than 31 months. This observation may help making decisions at this time.
Melanoma Res 1996 Apr
PMID:Prognostic factors for response and survival in patients with metastatic melanoma receiving immunotherapy. 879 Dec 76

During a systematic screening of melanoma infiltrating mononuclear and polynuclear immunological effector cells we employed 10 well characterized monoclonal antibodies, directed against leukocyte differentiation antigens, and the alkaline phosphatase conjugated, indirect, streptavidinbiotin immunocytochemical antigen detection technique and when necessary, the recently developed antigen retrieval method to enhance the intensity of the immunoreactivity to characterize the heterogeneous infiltrate of human primary (n = 30) and metastatic (n = 10) melanomas. Our study is the first to employ formalin fixed, paraffin embedded tissue sections in seeking to determine the ex vivo presence of tumor infiltrating leukocytes, including T lymphocytes, in human melanomas. We established the presence of some type of melanoma infiltrating host's immunological effector cells in all 40 observed melanoma cases'. More specifically, we found NK cells, macrophages and granulocytes in 30 out of 30 PMs and 10 out of 10 MMs. These effector cells represented the vast majority (> 80%) of the melanoma infiltrating immunocompetent cells. T lymphocytes were observed in 20 out of 30 PMs and 6 out of 10 MMs, but their numbers represented only between 5% to 10% of the heterogeneous leukocytic infiltrate. B cells were found in 22 out of 30 PMs and 8 out 10 MMs, their numbers representing less than 5%. Presence of cells of the dendritic reticulum, involved in antigen presentation was not determined in any of the observed PMs and MMs. There were more than enough macrophages and neutrophils, cells which are deeply involved in antigen presentation and, as previously mentioned, we found these cells within the melanomas. Thus defective antigen presentation cannot be the reason for the small proportion of T lymphocytes. What is to blame is probably the increased dedifferentiation of the melanoma immunophenotype (IP) to a degree that MHC class I molecules and the antigens complexed with them are lost and therefore there is nothing to be recognized by the T lymphocytes. In view of these results it is our-opinion that following the initial non-specific immune reaction, which may not be tumor specific, the specific immune response of effector T cells takes over. After significant IP changes by the majority of melanoma cells, including the internalization or shedding of MHC class I antigens, these highly specialized cells are no longer effective and the immune system responds by causing the reappearance of NK cells, macrophages and granulocytes. Thus, the relationship between melanoma and the host's immune system is evolutionarily dynamic: changes are readily made by either side when necessitated.
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PMID:Immunophenotypic characterization of human primary and metastatic melanoma infiltrating leukocytes. 904 4

The nm23/NDP kinase gene located on chromosome 17q has been proposed as metastasis suppressor gene in a variety of tumor types. Nm23 was initially isolated from the highly metastatic murine K-1735 melanoma cell line and levels of nm23 have been found to correlate inversely with metastatic potential in some tumors, but not in others. In the present immunocytochemical study, we investigated nm23 protein expression in 30 primary cutaneous malignant melanomas (CMs) and 10 metastases of malignant cutaneous melanomas (MMCMs) which had already metastasized to a distant site. We employed a sensitive, indirect, four to six step alkaline phosphatase conjugated biotin-streptavidin based immunocytochemical technique using the anti-nm23 affinity purified rabbit anti-human polyclonal antibody on formalin fixed paraffin embedded tissue sections of the malignant melanomas. We found nm23 expression in 24 out of 30 CMs with between 10% and 50% of the melanoma cells exhibiting immunoreactivity with the employed antibody. None of the ten MCMMs expressed nm23. As we described in a previous article (48), malignant melanoma is characterized by a high degree of cellular immunophenotype heterogeneity. In further support of this observation, we observed a diverse level of nm23, staining intensity in the cell subpopulations which comprises the tumor microenvironment. Nm23/NDP kinase has a diverse array of biological functions including roles in signal transduction and microtubule assembly. In our opinion, the many roles of nm23/NDP kinase are mainly involved in cell division and this may be the underlying reason that levels of this protein do not truly correlate with metastatic potential. Therefore, nm23 protein levels may correlate well with proliferative rate and degree of tumor specific dedifferentiation which are important parameters to be established in the early diagnosis, monitoring of neoplasma progression and efficacy of employed clinical trials, and the determination of prognosis of every neoplastic disease.
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PMID:Nm23/nucleoside diphosphate (NDP) kinase expression in human malignant melanomas: significance and implications in tumor biology. 906 3

Several growth factors and proto-oncogenes play a leading regulatory role during human carcinogenesis. In this systematic immunocytochemical study we observed the expression (overexpression) of the c-erbB-2 and c-erbB-3 oncoproteins in 30 primary cutaneous malignant melanomas (CMMs), 10 already metastasized malignant melanomas (MMMs) and 15 lymph-node negative breast carcinomas (BCs). Both oncoproteins were expressed as a result of either oncogene amplification or post-translational stabilization c-erbB-2 alone is unable to bind neuregulins, but it is able to act as a pan c-erbB receptor subunit. Heterodimerization between cerbB-2 and c-erbB-3 is required to initiate neuregulin directed signal transduction. We employed an indirect, four step streptavidinbiotin conjugated immunocytochemical technique for antigen detection. The visualization of the primary antigen-antibody reaction was carried out with alkaline phosphatase or immunoperoxidase labeling and the use of the appropriate enzymatic substrates. The presence of c-erbB-2 oncoprotein was detected in 12/30 CMMs, 8/10 MMMs and 6/15 BCs, while c-erbB-3 was identified in 14/30 CMMs, 7/10 MMMs and 6/15 BCs. The intensity of the cell membrane localized immunoreactivity was observed to be greater when the c-erbB-2 oncoprotein was targeted (A, AB and B). The c-erbB-3 oncoprotein was also detected in the cytoplasm with medium intensity (B, BC and C). Unfortunately, little is known concerning the range of oncoprotein overexpression after formalin fixation and paraffin embedding. We demonstrated overexpression localized to several cell clones within the oncoprotein positive population of malignant cells. The immunocytochemically defined extent of expression of both oncoproteins was between 10-40% (+ to +2) of the total cell population in the malignant melanomas and 20-35% (+2) of the total cell population in the BCs. In conclusion a) the results of the present study demonstrate the presence of c-erbB-2 and c-erbB-3 oncoprotein expression (overexpression) in melanoma and breast carcinoma, and b) oncogene receptor directed immunotherapy, as part of a more individualized anti-cancer treatment, represents a potentially valuable targeted treatment for the future.
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PMID:Clinical and prognostic significance of the expression of the c-erbB-2 and c-erbB-3 oncoproteins in primary and metastatic malignant melanomas and breast carcinomas. 913 92

Prostate-specific antigen (PSA), a 33 kD glycoprotein, was initially reported to be a tissue specific protein, detected in the seminal fluid and produced by normal and abnormal epithelial cells of the prostate gland, as well as other tissues in the human body. The expression of PSA has been described to be elevated during benign and neoplastic cell growth in the prostate, and in a number of other human malignancies. The presence and production of PSA in human primary cutaneous malignant melanomas (CMMs) and metastatic malignant melanomas (MMMs) has not been reported prior to the present study. We examined the expression of PSA employing a biotin-streptavidin based, alkaline phosphatase conjugated antigen detection technique in routine, neutral formalin fixed, paraffin-wax embedded, 3-4 microns thick tissue sections of 30 CMMs and 10 MMMs. Human postnatal thymic tissue, among others, was used as a negative tissue control, while normal prostate and prostate carcinomas (PCs) were included in the collection of antigen positive tissues. We observed the presence of PSA in 16/30 CMMs and 6/10 MMMs. The intensity of the staining was moderate (C to B) and localized to between 20% and 30% of the total tumor cell population in both CMMs and MMMs, with cells of similar immunoreactivity being clustered in groups within the tumor microenvironment. This result directly contradicts the previous opinion concerning the prostate epithelium specificity of PSA expression and production. The immunophenotype (IP) heterogeneity of malignant melanoma cells in further substantiated by the pattern of their PSA immunoreactivity. The establishment of the clinical significance of these findings necessitates further in vivo and in vitro research in malignant melanomas. PSA related, novel antineoplastic immunotherapy may also be recommended in the treatment of both CMMs and MMMs.
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PMID:Immunocytochemical detection of prostate specific antigen expression in human primary and metastatic melanomas. 921 12

The purpose of this study was to evaluate the expression of the Ca(2+)-binding S100 proteins S100A1, S100A2, S100A3, S100A4, S100A6 and S100B in normal skin. These immunohistochemical staining patterns were compared with those in melanocytic lesions. Paraffin-embedded tissue of normal skin adjacent to 26 naevi, 39 primary cutaneous melanomas and 14 cutaneous melanoma metastases was incubated with polyclonal antibodies against the recombinant human S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A6, S100B) using the alkaline phosphatase anti-alkaline phosphatase method. The S100A2 antibody stained the basal layer of the epidermis and hair follicles of normal skin. Four of 39 primary cutaneous melanomas were positive for S100A2, whereas none of the metastases or naevi showed any immunoreactivity. The S100A3 antibody only stained the inner root sheath cuticle of some hair follicles but no melanocytes or melanocytic lesions. Staining of S100A4 was weak and thus omitted to further analysis. S100A6 faintly labelled keratinocytes. Langerhans' cells, melanocytes and sweat glands. S100A6 immunoreaction was found in two of seven junctional naevi, five of seven compound naevi, and all dermal and blue naevi. There was an intense cytoplasmatic reaction for S100A6 in all primary cutaneous melanomas and in nine of 14 (64%) metastases, S100B was positive in melanocytes and Langerhans' cells, all primaries as well as in the metastases, S100A1 protein was not detected on any of the tissue specimens examined. Whereas S100B and S100A6 antibodies are useful markers for malignant melanoma, expression of S100A4 antibody is too low to be used for immunohistochemical staining. S100A1 and S100A3 antibodies are not expressed in melanocytic lesions and S100A2 is only found in selected tumours. The investigated S100 proteins, including S100B and S100A6, are also expressed in selected elements of normal skin. These findings are important for correct interpretation of staining patterns, when S100 antibodies are used as markers for melanoma or other tumours.
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PMID:Immunohistochemical localization of the Ca2+ binding S100 proteins in normal human skin and melanocytic lesions. 927 23

Monoclonal antibody 57B specifically detects MAGE-3 gene protein expression. MAGE-derived peptides are recognized by CD8+ T cells and applied in immunotherapy. We examined formalin-fixed, paraffin-embedded tissue of 61 melanoma (primary, n = 40; metastatic, n = 21) and 46 control cases (junctional, dermal, compound, Spitz, Reed, and balloon-cell nevi) by immunohistochemistry using the alkaline phosphatase anti-alkaline phosphatase method after antigen retrieval. Immunoreactivity was rated positive at 20 positive cells per tumor or more. Staining pattern was homogeneous, scattered, or focal. All control samples and internal controls were immunonegative. Staining with monoclonal antibody 57B showed a specificity of 100% with a sensitivity of 44%. Immunopositivity (overall, 44% of melanomas) increased along with tumor, node, and metastasis stage; pT1 showed 13%, pT2 22%, pT3a 29%, pT3b 45%, pT4 100%, pTxN1 60%, and pTxNxM1a 63% of samples positive. The staining pattern was homogeneous on pT1 to pT3a tumors, homogeneous or focal in pT3b and pT4a, and homogeneous, focal, or scattered in pTxN1 and pTxNxM1a. The frequency of immunopositivity relates well to data on mRNA expression using reverse transcriptase polymerase chain reaction in a subgroup analyzed by both methods. Monoclonal antibody 57B can be used to allow profiling of melanomas using routine archival tissue, when considering immunotherapeutic approaches involving MAGE-3-derived epitopes.
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PMID:MAGE-3 immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. 940 5

Monoclonal antibody T311 specifically detects tyrosinase protein expression. Tyrosinase-derived peptides are recognized by CD8+ T-cells and applied in immunotherapy. We examined formalin-fixed paraffin-embedded tissue of 50 melanoma (primary n=31, metastatic n=19) and 41 control cases (junctional, dermal, compound, Spitz, Reed, balloon-cell nevi) by immunochemistry using the alkaline phosphatase-anti-alkaline phosphatase method after antigen retrieval. Staining with mAb T311 showed a sensitivity of 94% for melanoma with a very high specificity for melanocytic cells. Immunopositivity (94% of melanomas overall) correlated inversely with clinical stage: clinical stage I and stage II showed 100%, stage III and stage IV 86% immunoreactivity each. Staining changed from an exclusively homogeneous pattern in early stages to a more heterogeneous pattern in later stages. Melanocytic control tissue like nevi of different subtypes all showed weak to moderate, homogeneous immunoreactivity with polarity towards the epidermis. RT-PCR ELISA analysis of short-term melanoma cell cultures displayed mRNA expression in only half of the originally immunopositive tumors only, suggesting rapid mRNA expression loss in culture. mAb T311 allows detection of melanoma-associated tyrosinase protein expression and thus profiling of melanomas using routine archival tissue suited for immunotherapy approaches involving tyrosinase derived epitopes.
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PMID:Tyrosinase immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution. 960 39

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including malignant melanomas, depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a dedifferentiated, malignant, highly invasive cellular immunophenotype (CIP) and distant metastases, as aspects of constant neoplastic progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during malignant melanoma (MM) related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 25 MMs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; +3 to +4) of EDG on endothelial cells was demonstrated in all MM cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. MMs, like most mammalian neoplasms, are characterized by extensive neovascularization, and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including MMs. The importance of TGF-beta in all of the various aspects of neoplastic transformation, as well as malignant disease progression should also be studied more extensively in the future.
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PMID:Immunocytochemical detection of endoglin is indicative of angiogenesis in malignant melanoma. 970 32


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