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: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The melanoma reactive chimeric 14.18 (ch14.18) antibody can mediate enhanced in vitro lysis of human M-21 melanoma cells. This study analyzes the antitumor effects and the in vivo binding of ch14.18 antibody with M-21 melanoma cells in severe combined immunodeficiency (SCID) mice. Outgrowth of tumors was prevented in 6/6 animals by the simultaneous subcutaneous injection of peripheral blood mononuclear cells (PBMC) [3 x 10(6) cells (2 animals); 10 x 10(6) cells (2 animals); and 30 x 10(6) cells (2 animals)], with 0.5 mg ch14.18, 1,500 U interleukin 2 (IL-2), and 10(6) M-21 cells. In contrast, 7 of 7 control mice that received M-21 cells alone, 7 of 7 mice that received M-21 cells and ch14.18, and 5 of 6 mice that received M-21 cells plus PBMC plus IL-2, grew subcutaneous tumors. The in vivo localization of ch14.18 was then evaluated in an intraperitoneal (i.p.) tumor model, where 0.3 cm melanoma nodules develop within 3 weeks after the i.p. administration of M-21 cells. Flow cytometric and immunohistochemical analysis revealed the GD2 antigen present throughout the tumor nodule. Intraperitoneal administration of 0.01, 0.1, or 1.0 mg of ch14.18 to SCID mice previously engrafted i.p. with M-21 cells resulted in detectable ch14.18 binding to tumor cells in vivo within 10 hours of antibody administration. Ch14.18 penetration was limited to approximately 20 cell layers, demonstrating that ch14.18 has limited access to some cells in large tumor nodules. This study demonstrates that the addition of ch14.18 to IL-2 and human effector cells can result in significant antitumor activity by preventing the establishment of tumor nodules. These results suggest that clinical testing of IL-2 plus ch14.18 might be most effective if used in the setting of microscopic residual disease. Therapies that enhance ch14.18 penetration into tumor nodules should be evaluated with ch14.18 for patients with advanced melanoma.
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PMID:In vivo binding and antitumor activity of Ch14.18. 1054 58

During past decades, knowledge of melanoma biology has increased considerably. Numerous therapeutic modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime example of poor treatment response that may, in part, be the consequence of activated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene products also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variety of human neoplasms, including malignant melanoma; therefore, it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a sensible approach to inhibit melanoma growth. To test this concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a recently discovered Ras antagonist that dislodges Ras from its membrane-anchoring sites, was evaluated. The antitumor activity of FTS was assessed both in vitro and in vivo in two independent SCID mouse xenotransplantation models of human melanoma expressing either wild-type Ras (cell line 518A2) or activated Ras (cell line 607B). We show that FTS (5-50 microM) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in human melanoma cells and Rat-1 fibroblasts, interrupts the Ras-dependent extracellular signal-regulated kinase in melanoma cells, inhibits the growth of N-Ras-transformed fibroblasts and human melanoma cells in vitro and reverses their transformed phenotype. FTS also causes a profound and statistically significant inhibition of 518A2 (82%) and 607B (90%) human melanoma growth in SCID mice without evidence of drug-related toxicity. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for human melanoma and possibly other tumors that either carry activated ras genes or rely on Ras signal transduction more heavily than nonmalignant cells.
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PMID:Novel Ras antagonist blocks human melanoma growth. 1057 Jan 91

The high-molecular-weight melanoma-associated antigen, HMW-MAA, has been demonstrated to be of potential interest for diagnosis and treatment of malignant melanoma. Murine monoclonal antibodies (mAb) generated in response to different epitopes of this cell-surface molecule efficiently localise to metastatic lesions in patients with disseminated disease. In this work, phage-display-driven selection for melanoma-reactive antibodies generated HMW-MAA specificities capable of targeting bacterial superantigens (SAg) and cytotoxic T cells to melanoma cells. Cynomolgus monkeys were immunised with a crude suspension of metastatic melanoma. A strong serological response towards HMW-MAA demonstrated its role as an immunodominant molecule in the primate. Several clones producing monoclonal scFv antibody fragments that react with HMW-MAA were identified using melanoma cells and tissue sections for phage selection of a recombinant antibody phage library generated from lymph node mRNA. One of these scFv fragments, K305, was transferred and expressed as a Fab-SAg fusion protein and evaluated as the tumour-targeting moiety for superantigen-based immunotherapy. It binds with high affinity to a unique human-specific epitope on the HMW-MAA, and demonstrates more restricted cross-reactivity with normal smooth-muscle cells than previously described murine mAb. The K305 Fab was fused to the superantigen staphylococcal enterotoxin A (D227A) [SEA(D227A)], which had been mutated to reduce its intrinsic MHC class II binding affinity, and the fusion protein was used to demonstrate redirection of T cell cytotoxicity to melanoma cells in vitro. In mice with severe combined immunodeficiency, carrying human melanoma tumours, engraftment of human lymphoid cells followed by treatment with the K305Fab-SEA(D227A) fusion protein, induced HMW-MAA-specific tumour growth reduction. The phage-selected K305 antibody demonstrated high-affinity binding and selectivity, supporting its use for tumour therapy in conjunction with T-cell-activating superantigens.
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PMID:Phage-selected primate antibodies fused to superantigens for immunotherapy of malignant melanoma. 1075 77

We examined parathyroid hormone-related peptide (PTHrP) production and regulation in both normal human melanocytes and in a human amelanotic melanoma cell line (A375). Northern blot and immunocytochemical analysis demonstrated that both cultured A375 cells and normal human melanocytes express PTHrP, but A375 cells expressed much higher levels of the peptide. PTHrP secretory rate increased at least 10-fold after treatment with 10% fetal bovine serum (100.2 +/- 2.8 pmol/10(6) cells vs. basal <15 pmol/10(6) cells) in proliferating A375 cells but only twofold in confluent cells. Treatment of A375 cells with increasing concentrations of 1, 25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or its low-calcemic analog EB-1089 revealed that EB-1089 was 10-fold more potent than 1, 25-(OH)(2)D(3) on inhibition of both cell proliferation and PTHrP expression. Furthermore, inoculation of A375 cells into the mammary fat pad of female severe combined immunodeficiency mice resulted in the development of hypercalcemia and elevated concentrations of plasma immunoreactive PTHrP in the absence of detectable skeletal metastases. Our study, therefore, demonstrates a stepwise increase in PTHrP expression when cells progress from normal to malignant phenotype and suggests that EB-1089 should be further evaluated as a therapeutic agent in human melanoma.
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PMID:Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes. 1100 3

The MGSA/GRO protein is endogenously expressed in almost 70% of the melanoma cell lines and tumors, but not in normal melanocytes. We have previously demonstrated that over-expression of human MGSA/GROalpha, beta or gamma in immortalized murine melanocytes (melan-a cells) enables these cells to form tumors in SCID and nude mice. To examine the possibility that the MGSA/GRO effect on melanocyte transformation requires expression of other genes, differential display was performed. One of the mRNA's identified in the screen as overexpressed in MGSA/GRO transformed melan-a clones was the newly described M-Ras or R-Ras3 gene, a member of the Ras gene superfamily. Over-expression of MGSA/GRO upregulates M-Ras expression at both the mRNA and protein levels, and this induction requires an intact glutamine-leucine-arginine (ELR)-motif in the MGSA/GRO protein. Western blot examination of Ras expression revealed that K- and N-Ras proteins are also elevated in MGSA/GRO-expressing melan-a clones, leading to an overall increase in the amount of activated Ras. MGSA/GRO-expressing melan-a clones exhibited enhanced AP-1 activity. The effects of MGSA/GRO on AP-1 activation could be mimicked by over-expression of wild-type M-Ras or a constitutively activated M-Ras mutant in control melan-a cells as monitored by an AP-1-luciferase reporter, while expression of a dominant negative M-Ras blocked AP-1-luciferase activity in MGSA/GRO-transformed melan-a clones. In the in vitro transformation assay, over-expression of M-Ras mimicked the effects of MGSA/GRO by inducing cellular transformation in control melan-a cells, while over-expression of dominant negative M-Ras in MGSA/GROalpha-expressing melan-a-6 cells blocked transformation. These data suggest that MGSA/GRO-mediated transformation requires Ras activation in melanocytes.
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PMID:MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression. 1103 Jan 54

The melanoma-associated Ag glycoprotein 100 was analyzed by the T cell epitope prediction software TEPITOPE. Seven HLA-DR promiscuous peptides predicted with a stringent threshold were used to load dendritic cells (DC), and induction of a proliferative response was monitored. PBMC of all nine donors including two patients with malignant melanoma responded to at least one of the peptides. The proliferative response was defined as a Th response by the selective expansion of CD4(+) cells, up-regulation of CD25 and CD40L, and IL-2 and IFN-gamma expression. Peptide-loaded DC also initiated a T helper response in vivo (i.e., tumor growth in the SCID mouse was significantly retarded by the transfer of PBMC together with peptide-loaded DC). Because the use of the TEPITOPE program allows for a prediction of T cell epitopes; because the predicted peptides can be rapidly confirmed by inducing a Th response in the individual patient; and because application of peptide-loaded DC suffices for the in vivo activation of helper cells, vaccination with MHC class II-binding peptides of tumor-associated Ags becomes a feasible and likely powerful tool in the immunotherapy of cancer.
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PMID:In vitro and in vivo induction of a Th cell response toward peptides of the melanoma-associated glycoprotein 100 protein selected by the TEPITOPE program. 1103 18

Natural killer (NK) cells play an important role in combating infectious and malignant diseases and interleukin-2 (IL-2) has been shown to promote proliferation and activation of NK cells in vitro and in vivo. Here we investigate the effects of local cationic lipid-mediated IL-2 gene transfer on intratumoral accumulation and activation of NK cells in a SCID mouse tumor model. UM449 human melanoma tumors in SCID mice received intratumoral injections of DMRIE/DOPE admixed with VR1103, a DNA plasmid encoding the gene for human IL-2. Dissagregated tumor cells were tested for IL-2 secretion and were characterized using antibodies to asGM1, MAC-1, and F4/80 antigens. Granzyme A, a proteolytic serine esterase, was also measured in tumor cell lysates. IL-2 secretion from tumors injected with VR1103:DMRIE/DOPE peaked at 48 h after injection and fell to baseline levels on day 8. Intratumoral granzyme A activity was significantly increased in tumors injected with IL-2 plasmid:DMRIE/DOPE complexes, but not by an irrelevant plasmid DNA:DMRIE/DOPE control. Importantly, the growth of UM449 tumors was slowed in VR1103:DMRIE/DOPE-injected tumors. These results indicate that local cationic lipid-mediated gene transfer of IL-2 induces activation of intratumoral NK cells and slows tumor growth.
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PMID:Cationic lipid gene transfer of an IL-2 transgene leads to activation of natural killer cells in a SCID mouse human tumor xenograft. 1106 17

Ultraviolet (UV) light is an epidemiological risk factor for melanoma, but its specific contribution to melanoma induction is not known. The first critical step of melanoma development, ie, the uncontrolled proliferation of melanocytes, may be induced by a combination of UV damage and an imbalance of growth factor production by cells in the immediate area of the melanocyte. Among several candidates, basic fibroblast growth factor (bFGF) is the major autocrine growth factor in melanoma and associated with tumor progression. Overexpression of bFGF via adenoviral gene transfer in human skin xenografted to severe combined immunodeficiency mice led to black-pigmented macules within 3 weeks of treatment. Immunofluorescence analysis demonstrated pathological hyperpigmentation, proliferation and hyperplasia of activated melanocytes, but no malignant transformation. Similar changes were observed in skin reconstructs. When bFGF was combined with UVB, pigmented lesions with hyperplastic melanocytic cells were detected, including a lesion with high-grade atypia resembling lentiginous forms of malignant melanoma. Donor-matched control grafts revealed no melanocytic changes. bFGF was overexpressed in dermal fibroblasts demonstrating the co-carcinogenic influence of paracrine-acting growth factors by cells of the microenvironment. This is the first report suggesting that an imbalance of physiological growth factor production in the skin may cause melanoma in combination with UVB.
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PMID:Basic fibroblast growth factor and ultraviolet B transform melanocytes in human skin. 1123 42

The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.
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PMID:Preclinical antitumor activity of the azonafide series of anthracene-based DNA intercalators. 1129 Aug 69

Application of immunocytokines [fusion proteins (FuPs)] where the cytokine has been coupled to an antibody may not produce the severe side effects frequently observed during systemic application of cytokines in cancer therapy. However, it has not been explored whether FuPs are sufficient for intratumoral activation of leukocytes or whether intratumoral versus systemic application may be of greater efficacy. Interleukin 2 (IL2) or tumor necrosis factor (TNF) coupled to an anti-epidermal growth factor receptor monoclonal antibody (IL2-FuP or TNF-FuP) were tested in SCID mice bearing a human epidermal growth factor receptor-positive melanoma transplant and being reconstituted with human HLA-matched peripheral blood leukocytes. Whole-body autoradiography revealed larger accumulation and prolonged retention of i.v. or intratumorally applied IL2-FuP or TNF-FuP compared with the antibody. Even with low doses of FuP, tumor growth was significantly retarded, with the survival time being further prolonged by the intratumoral application. Furthermore, outgrowth of the tumor was prevented in approximately 50% of mice as long as they received weekly injections of peripheral blood leukocytes concomitantly with the FuPs, which confirmed that it was the donor leukocytes activated in vivo that retarded tumor growth. An in vitro analysis revealed that the IL2-FuP supported mainly proliferation and lymphokine-activated killer cell activity, whereas TNF-FuP stimulated cytokine production and cytotoxic activity of monocytes and, to a low degree, of T cells. Both TNF-FuP and IL2-FuP significantly accumulated in the tumor, which led to retardation of tumor growth. The therapeutic effect was improved by intratumoral application. Importantly, the efficacy of both IL2-FuP and TNF-FuP depended on the induction of an immune response in vivo.
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PMID:Efficacy of local versus systemic application of antibody-cytokine fusion proteins in tumor therapy. 1130 50


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