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Berlin Brandenburg

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  • Melanoma
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  • 1
    Language: English
    In: Journal of Investigative Dermatology, August 2005, Vol.125(2), pp.201-206
    Description: It has been demonstrated that thalidomide's anti-angiogenic properties result in clear anti-tumor activity in a number of human malignancies. We studied thalidomide in a human melanoma severe combined immunodeficiency mouse xenotransplantation model. Thalidomide as a single agent showed a significant tumor reduction of 46% compared with the control group. Thalidomide combined with dacarbazine treatment markedly enhanced the anti-tumor effect of chemotherapy and showed a significant tumor reduction relative to the dacarbazine-only group (61%) and even more tumor reduction (74%) compared with the control group. We also measured clearly reduced levels of tumor necrosis factor-α in the thalidomide-treated group. A significantly lower microvessel density was encountered in the thalidomide treatment groups (thalidomide alone or combined with DTIC), underscoring the anti-angiogenic effect of thalidomide as a single agent as well as in combination with chemotherapy in this model. In line with these results, we observed a nearly 3-fold increase of apoptosis for the combination of thalidomide and DTIC compared with the rate of apoptotic cells in DTIC-only-treated melanoma xenotransplants. These data underline the rationale for combining dacarbazine—a cytotoxic agent—and thalidomide—an anti-angiogenic cytostatic agent—as a promising strategy for the treatment of melanoma.
    Keywords: Anti-Angiogenesis ; Apoptosis ; Chemotherapy ; Melanoma ; Microvessel Density ; Thalidomide ; Tnf-Α ; Medicine
    ISSN: 0022-202X
    E-ISSN: 1523-1747
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(1), p.e84417
    Description: Malignant melanoma is a life-threatening skin cancer increasingly diagnosed in the western world. In advanced disease the prognosis is grave. Growth and metastasis formation in melanomas are regulated by a network of cytokines, cytokine-receptors, and adhesion molecules. However, little is known about surface antigens and target expression profiles in human melanomas. We examined the cell surface antigen profile of human skin melanoma cells by multicolor flow cytometry, and compared their phenotype with 4 melanoma cell lines (A375, 607B, Mel-Juso, SK-Mel28). Melanoma cells were defined as CD45-/CD31- cells co-expressing one or more melanoma-related antigens (CD63, CD146, CD166). In most patients, melanoma cells exhibited ErbB3/Her3, CD44/Pgp-1, ICAM-1/CD54 and IGF-1-R/CD221, but did not express CD20, ErbB2/Her2, KIT/CD117, AC133/CD133 or MDR-1/CD243. Melanoma cell lines were found to display a similar phenotype. In most patients, a distinct subpopulation of melanoma cells (4-40%) expressed the erythropoietin receptor (EPO-R) and ErbB4 together with PD-1 and NGF-R/CD271. Both the EPO-R+ and EPO-R- subpopulations produced melanoma lesions in NOD/SCID IL-2Rgamma(null) (NSG) mice in first and secondary recipients. Normal skin melanocytes did not express ErbB4 or EPO-R, but expressed a functional KIT receptor (CD117) as well as NGF-R, ErbB3/Her3, IGF-1-R and CD44. In conclusion, melanoma cells display a unique composition of surface target antigens and cytokine receptors. Malignant transformation of melanomas is accompanied by loss of KIT and acquisition of EPO-R and ErbB4, both of which are co-expressed with NGF-R and PD-1 in distinct subfractions of melanoma cells. However, expression of EPO-R/ErbB4/PD-1 is not indicative of a selective melanoma-initiating potential.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: Journal of Investigative Dermatology, 2010, Vol.131(2), p.495
    Description: The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.
    Keywords: Animals–Pharmacology ; Antibiotics, Antineoplastic–Drug Effects ; Apoptosis–Physiology ; Apoptosis–Drug Effects ; Cell Cycle–Physiology ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Drug Effects ; Cell Proliferation–Physiology ; Cell Survival–Pharmacology ; Cell Survival–Pharmacology ; Disease Models, Animal–Metabolism ; Enzyme Inhibitors–Pathology ; Female–Physiopathology ; Furans–Antagonists & Inhibitors ; Humans–Metabolism ; Melanoma–Antagonists & Inhibitors ; Melanoma–Metabolism ; Melanoma–Pharmacology ; Mice–Pharmacology ; Mice, Nude–Drug Effects ; Multiprotein Complexes–Physiology ; Phosphatidylinositol 3-Kinases–Pharmacology ; Phosphatidylinositol 3-Kinases–Metabolism ; Proteins–Pathology ; Proteins–Physiopathology ; Pyridines–Antagonists & Inhibitors ; Pyrimidines–Metabolism ; Signal Transduction–Metabolism ; Signal Transduction–Metabolism ; Sirolimus–Metabolism ; Skin Neoplasms–Metabolism ; Skin Neoplasms–Metabolism ; Skin Neoplasms–Metabolism ; Tor Serine-Threonine Kinases–Metabolism ; Trans-Activators–Metabolism ; Trans-Activators–Metabolism ; Transcription Factors–Metabolism ; Transplantation, Heterologous–Metabolism ; Antibiotics, Antineoplastic ; Crtc2 Protein, Mouse ; Enzyme Inhibitors ; Furans ; Multiprotein Complexes ; Pi103 ; Proteins ; Pyridines ; Pyrimidines ; Trans-Activators ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 ; Phosphatidylinositol 3-Kinases ; Tor Serine-Threonine Kinases ; Sirolimus;
    ISSN: 0022-202X
    E-ISSN: 15231747
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  • 4
    Language: English
    In: International journal of cancer, 01 May 2002, Vol.99(1), pp.29-34
    Description: Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x(L) is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x(L) protein as a potential therapeutic target in melanoma, the influence of Bcl-x(L) expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x(L) in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p 〈 or = 0.05). In a parallel approach, reduction of Bcl-x(L) protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x(L) is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x(L) expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.
    Keywords: Antineoplastic Agents -- Therapeutic Use ; Apoptosis -- Drug Effects ; Cisplatin -- Therapeutic Use ; Melanoma -- Drug Therapy ; Oligonucleotides, Antisense -- Therapeutic Use ; Proto-Oncogene Proteins C-Bcl-2 -- Antagonists & Inhibitors ; Skin Neoplasms -- Drug Therapy
    ISSN: 0020-7136
    E-ISSN: 10970215
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  • 5
    Language: English
    In: International Journal of Cancer, 01 May 2002, Vol.99(1), pp.29-34
    Description: Malignant melanoma is a tumor that responds poorly to a variety of apoptosis‐inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl‐x is an antiapoptotic member of the Bcl‐2 family and is universally expressed in human melanoma. To evaluate the Bcl‐x protein as a potential therapeutic target in melanoma, the influence of Bcl‐x expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl‐x in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin‐induced apoptosis ( ≤ 0.05). In a parallel approach, reduction of Bcl‐x protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy‐induced apoptosis. These data suggest that Bcl‐x is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl‐x expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy. © 2002 Wiley‐Liss, Inc.
    Keywords: Melanoma ; Bcl‐X ; Antisense Oligonucleotide ; Chemoresistance ; Apoptosis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: John Wiley & Sons, Inc.
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  • 6
    Language: English
    In: Cancer research, 01 April 2002, Vol.62(7), pp.2098-103
    Description: The microphthalmia transcription factor MITF plays a pivotal role in the development and differentiation of melanocytes. The purpose of this work was to investigate the expression and function of the melanocyte-specific isoform MITF-M in human melanoma. We found that MITF-M is repressed in 8 of 14 established melanoma cell lines tested. Transfection of MITF-M into a melanoma cell line (518A2) lacking the M-isoform and into a permanent cell line established from normal melanocytes (NMel-II) resulted in slower tumor growth in a severe combined immunodeficient-mouse xenotransplantation model. The growth difference between vector control-transfected tumors derived from the NMel-II cell line (mean tumor weight +/- SD, 3.2 g +/- 1.13) and MITF-M (+) transfectants (mean tumor weight +/- SD, 1.1 g +/- 0.49) was significant (P = 0.018). The mean tumor weight of control-transfected 518A2 tumors was 0.99 g +/- 0.22 and of MITF-M (+) transfectants, 0.69 g +/- 0.32. The difference in growth between 518A2 controls and the MITF-M (+) transfectants was clear, however it did not reach statistical significance (P = 0.08). In addition to the growth-inhibitory effects, MITF-M expression led to a change in the histopathological appearance of tumors from epitheloid toward a spindle-cell type in vivo. These results indicate a role for the MITF-M isoform in the in vivo growth control and the phenotype of human melanoma. In conclusion, MITF-M may qualify as a marker capable of identifying subgroups of melanoma patients with different tumor biology and prognosis.
    Keywords: Transcription Factors ; DNA-Binding Proteins -- Biosynthesis ; Melanocytes -- Metabolism ; Melanoma -- Metabolism
    ISSN: 0008-5472
    E-ISSN: 15387445
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: Journal of Investigative Dermatology, October 2004, Vol.123(4), pp.664-669
    Description: Interferon-alpha (IFN-α) is widely used for the treatment of viral infections and primary cancers. In the present study, we investigated whether the anti-proliferative activity of IFN-α is capable of inhibiting melanoma tumor development in the absence of protective immune responses in a severe combined immunodeficiency (SCID) mouse model. Mice treated with either regular (100 μg/ 3 times per week) or pegylated (300 μg/ once weekly) human IFN-α 2a showed a marked reduction in tumor weight after 4 wk of treatment. Tumor weight in pegylated and conventional IFN-α-treated animals was reduced by 61% and 67%, respectively, as compared to saline control (both p≤0,01). A decrease of proliferation and an increase of apoptotic tumor cells were observed in IFN-treated tumors. DNA microarrays were applied to analyze transcriptional responses in tumors after 4 wk of treatment and a subset of about 90 genes was differentially expressed. Twenty-four novel and five known interferon-inducible genes were up- and 65 genes downregulated. A direct comparison of IFN-α and pegylated IFN-α did not reveal any significant differences in tumor growth inhibition indicating that this novel and more stable class of IFN is functionally equivalent. Despite the structural difference between pegylated and conventional IFN-α, both agents caused similar transcriptional responses in human melanoma xenotransplants.
    Keywords: Gene Expression Profiling ; Gene Chips ; Medicine
    ISSN: 0022-202X
    E-ISSN: 1523-1747
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  • 8
    Language: English
    In: Journal of Investigative Dermatology, February 2004, Vol.122(2), pp.387-391
    Description: For patients with advanced malignant melanoma, the 5 y survival rate with current treatment modalities is low. There is an urgent need for more effective therapeutic concepts. One approach with great potential is to stimulate the body's own immune defense to reject cancer cells using CpG oligonucleotides. Distinct oligonucleotides containing nonmethylated cytidine residues in cytidine-guanosine dinucleotides with particular flanking bases (CpG motifs) are capable of eliciting powerful immune stimulation by mimicking infectious disease. We evaluated the antitumoral effects of CpG oligonucleotides against human malignant melanoma xenografts in NOD/SCID mice. CpG oligonucleotides administered in single peritumoral subcutaneous injections three times per week resulted in elevated plasma levels of interleukin-12 and significant inhibition of the growth of established tumor xenografts by 60% (p〈0.016) compared to the saline control. In addition to this a significant invasion of macrophages into tumor xenografts and increased numbers of Langerhans-cell-derived dendritic cells in draining lymph nodes could be observed. Our findings demonstrate the antitumor activity of oligonucleotides containing immune-stimulatory CpG motifs in a xenotransplantation model with absent B, T cells and a lack of natural killer cell function.
    Keywords: Immunostimulation ; Dendritic Cells/Macrophages ; Antisense ; Oligonucleotides ; Medicine
    ISSN: 0022-202X
    E-ISSN: 1523-1747
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  • 9
    Language: English
    In: Molecular medicine (Cambridge, Mass.), December 2002, Vol.8(12), pp.877-84
    Description: Currently there is no information on the regulation of expression and physiological role of the anti-apoptotic protein Mcl-1 in cells of the melanocytic lineage. This study investigates the regulation and expression of Mcl-1 in human melanoma cells, which was recently found to be induced by betulinic acid, a compound with anti-melanoma and apoptosis-inducing potential. Mcl-1 phosphorthioate antisense oligonucleotides were used to investigate the effect of downregulating the expression of Mcl-1. Regulation of Mcl-1 expression was analyzed with the specific PI3-kinase inhibitors LY294002 and wortmannin and the inhibitor of MAP-kinase activation, PD98059. Western blot analysis was performed with anti ERK1/2, Mcl-1, Bak, Bcl-x and Bax antibodies. Activation status of PI-3 kinase and MAP-kinase pathways was investigated using phospho-Akt and phosphorylation-state independent Akt as well as phospho-MAP kinase, phospho-MEK and phospho-GSK-3alpha/beta antibodies. Upregulation of Mcl-1 in human melanoma cells by betulinic acid is mediated via a signal-transduction pathway that is inhibited by LY294002 and wortmannin. Betulinic acid-induced phosphorylation and activation of the Akt protein kinase was inhibited by LY294002. The inhibitor PD98059 reduced expression levels of Mcl-1 in melanoma cells and this effect was counteracted by betulinic acid. Downregulation of Mcl-1 by antisense oligodeoxynucleotides in combination with betulinic treatment led to a synergistic effect regarding growth inhibition. These results suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for survival and (ii) subject to dual regulation by the MAP- kinase pathway and a pathway involving protein kinase B/Akt, the latter of which is modulated in response to betulinic acid. This study provides an experimental foundation for future therapeutic strategies using anti-Mcl-1 antisense oligonucleotides in human melanoma.
    Keywords: Protein-Serine-Threonine Kinases ; Melanoma -- Metabolism ; Neoplasm Proteins -- Genetics ; Triterpenes -- Metabolism
    ISSN: 1076-1551
    E-ISSN: 15283658
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  • 10
    Language: English
    In: Anticancer research, 2005, Vol.25(4), pp.2697-703
    Description: Anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-x, can modulate radio- and/or chemosensitivity of human malignancies. Since no information is available on the role Mcl-1 may play in the radioresponse of tumor cells, the relationship between Mcl-1 expression and response to ionizing radiation (IR) was investigated using an antisense strategy. Human melanoma cells were treated with Mcl-1 antisense oligonucleotides (ASOs) and IR. The effects of antisense treatment alone or in combination with IR on proliferation, induction of apoptosis and clonogenic cell death were evaluated. ASO treatment in combination with IR reduced the mean cell numbers 9.5-fold compared to a 2.6-fold reduction after ASO treatment alone and a 1.6- fold reduction after IR alone. The percentages of apoptosis measured (means +/- SD) were 49% +/- 3.0 in antisense/IR-treated cultures compared to 1.3% +/- 0.5, 14.3% +/- 0.5, 7.3% +/- 1.1 and 10.3% +/- 0.6 in ASO controls, in antisense-treated, in IR-treated and in antisense control plus IR-treated cells, respectively. Colony formation assays demonstrated a synergistic effect of Mcl-1 down-regulation with IR. Mcl-1 expression affects the radioresistance of human melanoma cells.
    Keywords: Apoptosis -- Radiation Effects ; Melanoma -- Radiotherapy ; Neoplasm Proteins -- Antagonists & Inhibitors ; Oligonucleotides, Antisense -- Genetics ; Proto-Oncogene Proteins C-Bcl-2 -- Antagonists & Inhibitors
    ISSN: 0250-7005
    E-ISSN: 17917530
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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