Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of growth factors can stimulate the proliferation of human malignant melanoma cell lines. We investigated the effects of exogenous growth factors including basic fibroblast growth factor (bFGF), epidermal growth factor, transforming growth factor-alpha, insulin, insulin-like growth factor-I (IGF-I), acidic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta and nerve growth factor on six human metastatic melanoma cell lines. The mitogenic activity of each growth factor was tested using the [3H]thymidine incorporation assay. There was a variable response of the different cell lines to most growth factors. All of the melanoma cell lines tested responded to IGF-I. Furthermore, the effects of growth factors were additive, a combination of bFGF and IGF-I having the greatest effect on three melanoma cell lines tested. The quantitative radioimmunoassay for bFGF and [125I]bFGF binding assay revealed that all of these melanoma cell lines produced bFGF and expressed high affinity receptors for bFGF. A 20-mer antisense oligodeoxynucleotide against the AUG initiation site of the bFGF coding region inhibited the proliferation of Mel-Tang by 40% (p less than 0.0001) and that of SK-MEL-5 by 20% (p less than 0.005), suggesting that these cell lines are at least under partial autocrine control of proliferation by bFGF. The presence of bFGF receptors on a high percentage of melanoma cell lines makes these a potential target for melanoma therapy.
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PMID:Basic fibroblast growth factor production and growth factor receptors as potential targets for melanoma therapy. 132 54

A highly heterogeneous cell line, IIB-MEL-J, was established from a human metastatic melanoma. This cell line contains small cells, dendritic cells, and megacells with multiple nuclei. IIB-MEL-J expresses S 100, cytokeratin intermediate filaments and the gangliosides GD2 and GD3. It requires growth factors (insulin, EGF, and transferrin) and antioxidants for optimal growth. When plated under optimal conditions, IIB-MEL-J grows with a doubling time of 70-80 hours. The cells may be fractionated by Percoll gradient centrifugation into several subpopulations (A, B, and C) with different characteristics. Subpopulation A is the slowest growing, and most of the DNA-synthesizing cells are concentrated in fractions B and C. Every subpopulation expresses S 100 and cytokeratin intermediate filaments, whereas only subpopulation B and C express GD2 and GD3. Pigmented cells are concentrated mainly in subpopulation C. Cytogenetic analysis of IIB-MEL-J revealed extensive chromosomal alterations, including a highly heterogeneous chromosome number and chromosomal rearrangements, gains, losses, isochromosomes, and double minutes. This highly heterogeneous cell line may be helpful to study cellular differentiation and interaction between different subpopulations in human melanoma.
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PMID:Characterization of IIB-MEL-J: a new and highly heterogenous human melanoma cell line. 260 42

SPARC (secreted protein acidic and rich in cysteine) is an extracellular protein associated with tissues exhibiting high rates of cell proliferation and matrix remodeling. The current work shows that the human melanoma cell lines IIB-MEL-LES, IIB-MEL-IAN, and IIB-MEL-J and different human metastatic melanomas expressed high levels of SPARC mRNA and protein. By western blot analysis we detected a single secreted 42-kDa band in human diploid fibroblasts-conditioned medium and a 45- to 40-kDa doublet in the three melanoma cell lines and all the metastatic melanomas tested. Part of the melanoma samples and cell lines showed an additional doublet of 36-34 kDa. SPARC mRNA was expressed by the three established cell lines, 14 metastatic melanoma samples, and tumors raised in nude mice, and no spliced variants were found. The heterogeneous pattern of SPARC secreted by human melanoma cells is the result of post-translational glycosylation and a specific extracellular leupeptin-inhibitable cleavage. Unlike human fibroblasts, melanoma cells did not overexpress SPARC on addition of TGF-beta. Immunohistochemical analysis showed that SPARC was strongly expressed in 100% of primary melanomas (7 of 7) and metastatic melanomas (29 of 29), moderately expressed in most of the positive dysplastic nevi (13 of 14), and only weakly expressed in nevocellular nevi (4 of 25). Normal melanocytes did not express SPARC. The data suggest that the expression of SPARC is associated with the neoplastic progression of human melanoma.
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PMID:The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. 900 36

A cell line (UISO-H-MEL-2) was established from the neoplastic cells of a patient with malignant melanoma during the natural course of the patient's treatment. The melanoma cells express defined MHC Class I histocompatibility determinants including determinants specified by the HLA-A2 Class I allele, along with a common melanoma-associated T-cell epitope derived from the tyrosinase gene. The gene for human interleukin-2 (IL-2) was transduced into the cells with a provirus (pZipNeoSVIL-2), packaged in GP + envAM12 cells. Integration of the IL-2 gene into genomic DNA of the transduced cells and its expression were established. The IL-2-secreting cell line (UISO-H-MEL-2-IL-2) was found to be free of recombinant retroviruses and other infectious agents. The IL-2-secreting cells will be subjected to 5000 rads X-irradiation and administered to 12 informed patients with metastatic malignant melanoma in a Phase I toxicity study. The dose of X-irradiation was sufficient to inactivate one hundred percent of the cells, but insufficient to completely inhibit IL-2 synthesis during a fourteen-day period of analysis. Patients who have failed all standard forms of treatment will become eligible for inclusion in the study if they develop metastatic melanoma, and if their tumor cells express products of the tyrosinase gene. The patients will differ with the cellular immunogen at no less than three of six MHC Class I alleles, but will share identity at the HLA-A2 Class I allele. The patient's antimelanoma immune response to the injected cells will be determined by both in vivo and in vitro parameters. Background studies performed in inbred mice indicate that X-irradiated IL-2-secreting cells that express both melanoma-associated antigens and allogeneic Class I histocompatibility antigens are more antigenic in terms of their capacity to induce an antimelanoma response than X-irradiated IL-2-secreting melanoma cells. Of significance for the future potential of this form of therapy in melanoma patients, the period of survival of mice was established melanoma treated with the IL-2-secreting allogeneic cells was significantly (P < 0.001) longer than that of untreated animals, or animals treated with X-irradiated melanoma cells. An analogous protocol was reviewed and approved by the Recombinant DNA Advisory Committee of the National Institutes of Health.
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PMID:Phase I evaluation of interleukin-2-transfected irradiated allogeneic melanoma for the treatment of metastatic melanoma: appendix 1: protocol. 932 73

Metastatic melanoma, compared with other cancers, appears to be unusual because of its low frequency of p53 mutations and prevalence of wild-type p53 protein in advanced malignancy. Here, we examined the effects of wild-type and mutated p53 (143 Val-Ala) on tumorigenic and metastatic potential of two human melanoma cell lines. The cell line UISO-MEL-4 contains wild-type p53 and is tumorigenic, whereas UISO-MEL-6 lacks p53 and produces lung and liver metastasis upon s.c. injection into athymic mice. Our study showed that UISO-MEL-4 stably transfected with wild-type p53 cDNA driven by cytomegalovirus promoter-enhancer sequences expressed high levels of p53 and p21 and formed s.c. tumours in vivo. Mutated p53 (143 Val-Ala) expression, on the other hand, inhibited tumour growth in 50% of cases and produced significantly slower growing non-metastatic tumours. Reduced tumour growth involved necrotic as well as apoptotic cell death. Inhibition of tumour growth was abrogated by the addition of Matrigel (15 mg ml(-1)). With UISO-MEL-6 cells, stably transfected with mutant p53, tumour growth was delayed and metastasis was inhibited. In soft agar colony formation assay, both wild-type and mutant p53 transfectants reduced anchorage-independent colony formation in vitro. These data suggest that mutated (143 Val-Ala) p53, which retains DNA binding and some of the transactivation functions of the wild-type p53 protein, suppresses tumorigenic and metastatic potentials of human melanoma cell lines in vivo.
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PMID:Suppression of tumorigenic and metastatic potentials of human melanoma cell lines by mutated (143 Val-Ala) p53. 964 36

The role of growth factor receptors in regulating the progression of human melanocytes toward tumorigenicity and ultimately a malignant phenotype is poorly understood. In particular, the autocrine and paracrine influences that modulate cellular invasion and extracellular matrix (ECM)-degradative enzymes in melanoma cells remain undefined at the molecular level. The low-affinity p75 neurotrophin receptor (p75NTR), a cysteine-rich transmembrane glycoprotein, is frequently expressed in advanced stages of human melanoma, but the biological consequences of this expression are unknown. p75NTR can enhance the invasive potential of brain-metastatic melanoma cells in vitro. We have extended here these results and related the level of p75NTR in human metastatic melanoma cells to their invasive potential to target organs other than brain. Fluorescence activated cell sorting (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W) had differential p75NTR contents, whereas SK-MEL-147 cells had elevated amounts of p75NTR. Two other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point mutations in the p75NTR transmembrane domain had reduced (SK-MEL-94) or absent (SK-MEL-110) p75NTR. We also examined these cell lines for presence of TrkA receptor, the high-affinity receptor for nerve growth factor (NGF), the prototypic neurotrophin. No TrkA receptor expression was detected in any of the cell lines. The extent of p75NTR expression correlated with the capability of NGF to promote cellular invasion and with production of heparanase, an important ECM-degradative enzyme. Melanoma cells sorted for high p75NTR expression (p75NTR-H cells) had markedly greater (9- to 13-fold increase) invasive capabilities in response to NGF exposure than those sorted for low p75NTR expression (p75NTR-L cells). Additionally, NGF induced a 8- to 10-fold increase of heparanase activity in p75NTR-H cells. Thus, we propose that p75NTR-mediated trophic support profoundly affects melanoma cell invasion to neurotrophin-rich organs.
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PMID:Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells. 1036 Aug 29

The presence and characteristics of androgen receptors (ARs) have been described by our group in one human melanoma cell line. We have now investigated their presence in two other human melanoma cell lines, IIB-MEL-LES and IIB-MEL-IAN, as well as in biopsies from human metastatic melanoma. Scatchard analysis revealed a single binding component for both cell lines, the apparent dissociation constant obtained being 15 nM, with a binding capacity of 280 fmol/mg total cell protein, for IIB-MEL-LES cells and 14 nM, with a binding capacity of 206 fmol/mg total cell protein for IIB-MEL-IAN cells. When specificity was assessed, not only androgen and anti-androgen but also non-androgenic compounds were able to compete for [3H]R1881 binding, as seen before. When immunocytochemistry of IIB-MEL-LES and IIB-MEL-IAN cells was performed for ARs, both cell lines were deeply stained in the nucleus, whereas no staining was found for oestrogen or progesterone receptors. Every specimen of melanoma metastases tested for the presence of ARs was deeply stained, and in the majority the intensity of the staining was high. Several hormones and anti-hormones were tested for their ability to affect cell proliferation. In both cell lines, testosterone, dihydrotesterone, oestradiol and progesterone significantly stimulated cell proliferation, and this was reversed by hydroxyflutamide, bicalutamide or tamoxifen.
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PMID:Androgen receptors in human melanoma cell lines IIB-MEL-LES and IIB-MEL-IAN and in human melanoma metastases. 1245 42

The chimeric KM871 monoclonal antibody targets the GD3 disialoganglioside antigen and is under investigation for its immunotherapeutic potential in melanoma. Preclinical and phase I studies have demonstrated the biodistribution and specific tumour targeting of KM871 to metastatic melanoma in vivo, with a long half-life and lack of immunogenicity making it an attractive candidate for further clinical trials. In vitro studies have demonstrated KM871 induces high levels of cytotoxicity in both antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. In order to investigate the potential for cytokine upregulation of KM871-mediated ADCC, freshly isolated healthy donor PBMC effector cells were cultured in the presence or absence of the cytokines interleukin-2, interleukin-12 and granulocyte/macrophage-colony stimulating factor and the ADCC determined over a 10-day period. In the absence of these cytokines, ADCC activity of 1 micro g/ml KM871 on (51) Cr-labeled SK-MEL-28 target cells could not be detected after 72 hrs of culture of PBMC effector cells in media. In contrast, ADCC mediated by KM871 was significantly enhanced and maintained for the 10-day study period upon culturing PBMCs with media containing IL-2 and/or IL-12, but not with GM-CSF. FACS analysis of the effector cell population indicated CD3-/CD16+56+ NK cells were primarily responsible for the KM871-mediated ADCC activity and a direct correlation was observed between the percentage of NK cells and the level of cytotoxicity mediated by the PBMCs. Furthermore, ADCC was significantly reduced using NK-depleted PBMCs. These results suggest combining IL-2 or IL-12 with KM871 may enhance KM871 immune-mediated cell killing in patients with metastatic melanoma.
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PMID:Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity mediated by chimeric anti-GD3 monoclonal antibody KM871. 1274 58

The incidence of melanoma is rising, and therapeutic options for metastatic melanoma are limited. We report the results of experimental melanoma therapy with 188-Rhenium-labeled melanin-binding decapeptide ((188)RE-HYNIC-4B4) and a comprehensive safety evaluation of this treatment. (188)RE-HYNIC- 4B4 bound only to nonviable eumelanotic MNT1 and pheomelanotic SK-28-MEL human melanoma cells in vitro, as determined by immunofluorescence, which is consistent with the inaccessibility of intracellular melanin in live cells, and suggests specificity for tumors with a significant amount of extracellular melanin. Administration of 1 mCi (188)RE-HYNIC-4B4 to MNT1 tumor-bearing mice significantly slowed tumor growth, with the therapeutic effect being a result of specific binding to tumor melanin, as irrelevant (188)RE-labeled decapeptide did not produce therapeutic gain. Repeated doses of (188)RE-HYNIC-4B4 had a more profound effect on tumor growth than a single dose. Treatment of tumors with 0.3-0.4 cm diameter was more effective than of larger ones (0.5-0.7 cm). There was no difference in uptake of (188)REHYNIC- 4B4 in melanized tissues of black C57BL6 mice and no histologically apparent damage to these tissues in comparison with white BALB/C mice. Treatment of C57BL6 mice with (188)RE-HYNIC-4B4 did not change their behavior, as established by SHIRPA protocol, and did not cause damage to neurons and glial cells. These results indicate that radiolabeled melanin-binding peptides are efficient and safe in treatment of melanoma and could be potentially useful against this tumor.
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PMID:Radiolabeled melanin-binding peptides are safe and effective in treatment of human pigmented melanoma in a mouse model of disease. 1670 32

Identifying factors that determine the sensitivity or resistance of cancer cells to cytotoxicity by antibody-drug conjugates is essential in the development of such conjugates for therapy. Here the monoclonal antibody L49 is used to target melanotransferrin, a glycosylphosphatidylinositol-anchored glycoprotein first identified as p97, a cell-surface marker in melanomas. L49 was conjugated via a proteolytically cleavable valine-citrulline linker to the antimitotic drug, monomethylauristatin F (vcMMAF). Effective drug release from L49-vcMMAF likely requires cellular proteases most commonly located in endosomes and lysosomes. Melanoma cell lines with the highest surface p97 expression (80,000-280,000 sites per cell) were sensitive to L49-vcMMAF whereas most other cancer cell lines with lower p97 expression were resistant, as were normal cells with low copy numbers (< or = 20,000 sites per cell). Cell line sensitivity to L49-vcMMAF was found by immunofluorescence microscopy to correlate with intracellular fate of the conjugate. Specifically, L49-vcMMAF colocalized with the lysosomal marker CD107a within sensitive cell lines such as SK-MEL-5 and A2058. In contrast, in resistant cells expressing lower p97 levels (H3677; 72,000 sites per cell), L49-vcMMAF colocalized with caveolin-1, a protein prominent in caveolae, but not with CD107a. Thus, for antibody-drug conjugates targeting p97, antigen level and trafficking to the lysosomes are important factors for achieving robust in vitro cytotoxicity against cancer cells. Immunohistochemical analysis with L49 revealed that 62% of metastatic melanoma tumors had strong staining for p97. Overexpression of p97 in melanoma as compared with normal tissue, in conjunction with the greater sensitivity of tumor cells to L49-vcMMAF, supports further evaluation of antibody-drug conjugates for targeting p97-overexpressing tumors.
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PMID:Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. 1681 6


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