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)

We evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP's anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme's active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP's antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.
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PMID:Ancylostoma caninum anticoagulant peptide blocks metastasis in vivo and inhibits factor Xa binding to melanoma cells in vitro. 960 44

Cytotoxic effector cells interact with target cells through various mechanisms. CTLs use the antigen-specific T cell receptor, whereas Fc receptor-positive natural killer cells use this receptor to interact with antibody-coated target cells. We evaluated the tumor-binding and lymphocyte-activating capability of a recombinant fusion protein consisting of a tumor-selective human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin-2 (IL2) (ch14.18-IL2). This fusion protein bound specifically to GD2-positive melanoma and neuroblastoma tumor cell lines, and its IL2 component stimulated in vitro proliferation of an IL2-dependent cell line, as well as peripheral blood mononuclear cells, in healthy control individuals and in cancer patients receiving continuous infusion of IL2. The IL2 presented by the fusion protein, when bound to tumor cells, induced proliferation of IL2-responsive cells as well as a comparable amount of soluble IL2 did. This suggests that localization of IL2 at the site of contact between tumor and effector cells is an effective way of presenting this cytokine to IL2-responsive cells. The ch14.18-IL2 fusion protein also mediated antibody-dependent cellular cytotoxicity with Fc receptor-positive effector cells to an extent similar to ch14.18. These results, together with those of previous studies documenting antitumor efficacy against human tumor xenografts in SCID mice and GD2-positive murine tumors in immunocompetent syngeneic mice, suggest that the ch14.18-IL2 fusion protein should be tested in Phase I and II trials in patients with GD2-positive tumors.
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PMID:Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14.18-IL2). 981 54

Gene transfer is a potentially powerful tool for the treatment of a wide variety of diseases. The transfer of these genes is achieved by utilizing a variety of vectors, including retroviral, adenoviral, adeno-associated virus (AAV) and a number of non-viral mechanisms. Numerous studies have successfully demonstrated transduction of genes into target cells with a variety of vectors, and have provided 'proof-in-principle' that gene transfer can result in prolonged in vivo expression of transduced genes, albeit at low quantities. Furthermore, gene marking studies in acute myeloblastic leukemia (AML), chronic myeloid leukemia (CML) and neuroblastoma have elegantly demonstrated that gene-marked tumor cells contribute to relapse following autologous transplantation. However none of the studies examining the therapeutic benefit of gene therapy has definitively demonstrated a clinically meaningful benefit. Nonetheless, the results of studies involving gene transfer for severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), melanoma and lung cancer highlight the potential benefit of this strategy. This review will discuss mechanisms of achieving gene transfer into target cells. It will examine some of the pre-clinical and clinical results to date and will discuss some of the potential uses of gene transfer for therapeutic purposes.
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PMID:Gene transfer: a review of methods and applications. 983 7

The adoptive transfer of tumor-specific cytotoxic T cells (CTL) offers a promising perspective in cancer immunotherapy. However, the ex vivo-generated T lymphocytes are mostly IL-2-dependent. Here we explored the possibility of circumventing the requirement for IL-2, known for severe side effects in the patient, and of simultaneously targeting the CTL towards the tumor by the use of 2 bi-specific antibody fragments. As a model system, we used SCID mice bearing an s.c.-implanted human melanoma line (BLM-gp100) and in vitro-generated CTL specific for the gp100-derived immunogenic peptide YLEPGPVTA, which were injected i.v. with delay. To maintain the cytotoxic potential of the transferred CTL, 2 bi-specific antibody (biAb) fragments were generated which bound with one arm either CD3 or CD28, a combination known to support the activation of CTL. For targeting the CTL, both biAbs contained the F(ab') part of HD-Me13, an antibody recognizing p97, a non-immunogenic melanoma-associated surface molecule. In vitro and in vivo, the addition of the 2 biAbs increased the cytotoxic potential of the gp100-specific CTL and supported their clonal expansion in the absence of IL-2. Correspondingly, significantly higher numbers of CTL were recovered from melanoma-bearing SCID-mice that received the 2 biAb than from mice treated with the CTL only. In animals treated with CTL plus both biAbs, the primary tumor did not grow, and none of the mice developed metastases. Thus, this set of bi-specific antibody fragments was proved to target effector cells in the tumor-bearing host and to efficiently support in vivo clonal expansion and cytolytic activity of in vitro-generated CTL.
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PMID:Human melanoma therapy in the SCID mouse: in vivo targeting and reactivation of melanoma-specific cytotoxic T cells by bi-specific antibody fragments. 1020 66

The cell surface glycoprotein MUC18MCAM/CD146 was originally defined as a marker of melanoma progression and has been suspected to be directly linked to the metastatic process of this malignancy. In order to address this question, 2 MCAM negative human melanoma cell lines, SK-2 and XP44RO(Mel), were transfected with MCAM-encoding cDNA. Surface MCAM expression on SK-2 and XP44RO(Mel) transfectants was similar to that observed in naturally occurring MCAM positive human melanoma cells and transfectants demonstrated MCAM-dependent increase in homotypic adhesion in vitro. The growth behavior of 7 MCAM transfectants and their respective vector controls was evaluated in SCID mice. Tumor size at 4-5 weeks after s.c. implantation was highly variable, but did not correlate with MCAM expression. Despite massive primary tumor formation at the injection site, no spontaneous metastasis was observed with any of the investigated MCAM transfectants. The influence of MCAM expression on lung metastases formation in an experimental metastasis assay was system dependent, converting only XP44RO(Mel) transfectants into metastatic cells, although increased homotypic adhesion, leading to formation of tumor cell clusters, was observed with transfectants of both cell lines in vitro. Our findings indicate that MCAM expression of human melanoma cells has an influence on later stages of the metastatic process only, namely, extravasation and establishment of new foci of growth, but is per se not sufficient for this process.
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PMID:Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice. 1036 44

Intravenous (i.v.) Ig is the human serum Ig fraction that is mainly composed of IgG prepared from plasma pools of over 15,000 healthy blood donors and is suitable for i.v. use. High-dose i.v. Ig is currently used to treat patients with diverse autoimmune conditions. Autoimmunity and malignancy co-exist frequently, and share etiological and pathological mechanisms. Since the two diseases are similarly treated, we studied the efficacy of i.v. Ig as a treatment for malignant conditions. The administration of i.v. Ig to mice inoculated i.v. with melanoma or sarcoma cells induced a statistically significant inhibition of metastatic lung foci and prolongation of survival time. Similar results were seen with SCID mice inoculated with SK-28 human melanoma cells. In a different model, melanoma was induced in the foot pad, followed by leg amputation, after the development of the tumor lesion. A lower number of melanoma recurrences and prolongation of survival time were demonstrated in the i.v. Ig-treated groups. In vitro studies revealed that i.v. Ig was found to stimulate the production of IL-12, an anti-tumor and anti-angiogenic cytokine. Moreover, it enhanced NK cell activity, thus explaining its beneficial effect in SCID mice (which lack B and T but possess NK cells). The results indicate that i.v. Ig acts as an anti-tumor agent. Since it has only minor side effects and is used extensively for other clinical conditions, i.v. Ig may be considered as a potential therapy for the prevention of tumor spread in humans.
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PMID:Gamma-globulin inhibits tumor spread in mice. 1042 82

Tissue factor (TF) is a transmembrane glycoprotein that complexes with factor VIIa to initiate blood coagulation. It was reported in an earlier study that expression of high levels of TF in a human melanoma cell line promotes metastasis, and that the cytoplasmic domain of TF is required for this metastatic effect. To analyze the functions of the cytoplasmic and extracellular domains of TF in metastasis, two TF mutants were constructed; in one mutant alanine was substituted for each of the three serine residues in the cytoplasmic domain, preventing phosphorylation; in the other mutant alanine was substituted for four key residues in the extracellular domain, preventing binding of factor VIIa and consequently eliminating the initiation of blood coagulation by the TF-VIIa complex. Melanoma lines expressing high levels of either mutant form of TF were weakly metastatic in SCID mice, indicating that phosphorylation of the cytoplasmic domain and formation of a complex with VIIa by the extracellular domain are required for the full metastatic effect of TF. It was also found that increasing TF expression in human melanoma cells does not increase expression of vascular endothelial growth factor or promote growth and vascularization of tumors derived from the melanoma cells, suggesting that TF acts by a mechanism other than angiogenesis to promote metastasis.
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PMID:Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. 1045 59

Malignant melanoma is the deadliest form of skin cancer. Previous studies have shown that the incidence of ras mutation increases with progression of melanoma, but that such mutations may not be present in the earliest radial growth phase melanomas. Recently it has been proposed that introduction of ras mutations into cells deficient in tumour suppressor genes such as p16 (INK4a) is sufficient to induce characteristics of cellular transformation such as anchorage-independent growth and tumour formation in vivo. To test this hypothesis in human melanoma, mutant N-ras, mutant H-ras or wild-type H-ras genes were transfected by electroporation into WM35 cells, a p16-deficient human melanoma cell line of low invasive potential. Increased expression of mutant ras p21 enhanced anchorage-dependent cell growth on tissue culture plastic. In addition, overexpression of mutant N-ras and H-ras, but not of wild-type H-ras, increased the experimental invasive potential, inducing anchorage-independent growth in soft agar, increasing cell motility measured by time-lapse video microscopy, and increasing invasiveness through reconstituted basement membranes. Finally, overexpression of mutant H-ras in melanoma cells was shown to increase tumorigenicity and to induce cachexia when H-ras transfected cell lines were injected subcutaneously in severe combined immunodeficiency (SCID) mice. Thus the addition of activating ras mutations to a melanoma cell line already deficient in p16 leads to enhanced proliferation, survival and migration in vitro and to enhanced subcutaneous tumour formation in vivo. This phenotype is typical of the behaviour of vertical growth phase (VGP) melanoma, and we propose that activation of the ras signalling pathway in the presence of deletions in p16 or related tumour suppressors can induce the VGP melanoma phenotype.
Melanoma Res 1999 Jun
PMID:Overexpression of mutant ras in human melanoma increases invasiveness, proliferation and anchorage-independent growth in vitro and induces tumour formation and cachexia in vivo. 1046 84

Activation of the N-ras gene by point mutation occurs in about 15% of all human melanomas. In recently established severe combined immunodeficiency (SCID) mouse xenotransplantation models for human melanoma, we demonstrated that mutated N-ras not only contributes to tumour growth by enhancing cellular proliferation, but also by blocking apoptosis. Mutated N-ras overexpression protected human melanomas from naturally occurring apoptosis and, in a more pronounced way, from chemotherapy-induced apoptosis in vitro and in vivo. Given the potential clinical importance of these findings we sought to determine the underlying mechanism. We found that mutated N-ras specifically upregulates the expression of the anti-apoptosis gene bcl-2 in two human melanoma cell lines in vitro and in SCID mice. Neither the expression of the anti-apoptotic protein Bcl-xL nor that of the pro-apoptotic proteins Bax and Bak were altered in cells expressing mutated N-Ras. The increase in Bcl-2 expression mediated by mutated ras therefore qualifies as a rational explanation for the enhanced chemoresistance of human melanoma expressing mutated N-Ras.
Melanoma Res 1999 Aug
PMID:Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. 1050 52

Induction of a helper T (TH)-cell response is a critical element in the generation of anti-tumor immunity. The majority of immunotherapeutic approaches have so far been concerned with the generation of cytotoxic T lymphocytes (CTLs). This also accounts for gp100, a melanoma-associated protein which induces a potent CTL response. Because of the high immunogenicity of gp100, we considered it of special interest to explore the feasibility of generating gp100-specific TH cells. Human dendritic cells (DCs) were loaded with recombinant gp100 protein, and the response of autologous TH cells was evaluated in vitro and in vivo. We have observed that gp100 peptides can be presented by DCs of certain MHC class II haplotypes, which led to proliferation and cytokine production of TH-1 cells in vitro. Furthermore, transfer of gp100 protein-loaded human DCs into SCID mice also induced proliferation of autologous, unprimed peripheral blood leukocytes (PBLs) and selective expansion of TH cells. When human T cells from the spleen of SCID mice were recovered and restimulated in vitro, they strongly proliferated in response to gp100-loaded DCs, while showing minimal proliferative activity in response to DCs loaded with a control antigen. Thus, it is possible to induce an efficient MHC class II-restricted TH response by in vitro stimulation or in vivo vaccination with DCs which have been loaded with a purified tumor-associated antigen.
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PMID:Recombinant gp100 protein presented by dendritic cells elicits a T-helper-cell response in vitro and in vivo. 1050 93


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