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)

A patient with chronic renal failure received a closely matched cadaveric kidney. Approximately 3 months after transplantation, the patient developed a metastatic malignant melanoma. A large retroperitoneal mass consisting of large pleomorphic polygonal neoplastic cells was found close to the donated kidney. This tumor was diagnosed as a malignant melanoma. DNA analysis of this tumor, the donated kidney, and the recipient indicated that the melanoma originated from the donor. Although this is not the first report of a donated melanoma, it is the first report of definitive DNA analysis of the origin of the malignant cells.
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PMID:Identification of donor melanoma in a renal transplant recipient. 136 74

Recombinant DNA technology was used to insert a fetal liver genomic library ApaI fragment encoding for human erythropoietin (Epo) into Bowes melanoma cells. The cells expressed the erythropoietin gene, and Epo was secreted into the culture medium together with the normally-secreted tissue plasminogen activator. Attempts to grow the cells in glass spinners in Dulbecco's medium supplemented with fetal bovine serum produced cell aggregates growing in suspension. When calcium-free suspension culture media (Joklik, DME-S, McCoy 5A-S) were used, single cell suspension cultures were obtained and high Epo production observed. When attempts were made to scale up the small glass spinners, poor growth or Epo production occurred unless the vessels were aerated. This was shown to be because of the drop in pH, possibly due to CO2 accumulation, rather than due to oxygen depletion. It was shown that a semi-continuous operation could be achieved in aerated 8-1 spinners fitted with either a conventional stirrer or a vibromixer agitator. The system was scaled up to a 100-1 stainless steel vessel fitted with a vibromixer agitator. This system was operated for over 4 months with weekly harvests producing over 100 million units of Epo in about 1000-1 of culture fluid. Interference by the serum proteins with downstream purification of the hormone from the culture fluid made the use of serum-free media highly desirable. Studies showed that the Epo was produced in serum-free systems containing peptones.
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PMID:Production of recombinant human erythropoietin in Bowes melanoma cells in suspension culture. 136

Synergy, when it can be convincingly established, is an effective strategy for the development of novel drug combinations. We have evaluated the interaction between 2'-deoxy-5-azacytidine (DAC) and 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) based on our hypothesis that DAC, through DNA hypomethylation, might increase the transcription of topoisomerase I (topo I) leading to increased sensitivity to topotecan. Five human tumor cell lines, A375 melanoma, DX-3 melanoma, DMS4C non-small cell lung carcinoma, UP-1 unknown primary adenocarcinoma, SN12C renal carcinoma, and the murine CT-26 tumor cell line, were studied. Drug interactions were assessed using the multiple drug effect analysis of Chou and Talalay (Chors, T-C, and Talalay, P. Adv. Enzyme Regul., 22:27-54, 1984.). A synergistic interaction was documented in four human cell lines and the murine CT-26 line. An antagonistic interaction was observed with the SN12C cell line. The toxicology and efficacy of this combination were analyzed using CT-26 in BALB/c mice. Various treatment schedules were studied, including: single doses of each agent; single sequential combination treatments where DAC was administered followed by topotecan 24 h later; and multiple sequential treatments where DAC and topotecan were administered on days 1, 2, 8, and 9. Efficacy studies showed that the single sequential combination of DAC (50 mg/kg) and topotecan (10 mg/kg) resulted in tumor growth delay as compared to single doses of DAC (50 mg/kg) or topotecan (10 mg/kg). When the multiple sequential combination schedule was used, the antitumor effect was more pronounced. In that experiment 50% of the control animals had tumors of 20 mm by day 28. For animals receiving a single sequential treatment with DAC and topotecan, the median time until the mean tumor size reached 20 mm was 38 days, and for the group with multiple sequential combination treatments the time was 51 days. Studies of the mechanism of the interaction showed that the activity of topotecan versus each cell line correlated with the topo I activity in nuclear extracts However, there was no correlation between topo I levels and synergy and no reproducible increase in topo I activity following exposure to DAC. Thus, while the exact mechanism of the interaction remains unclear, DAC can be effectively combined with topotecan to enhance antitumor activity.
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PMID:Synergistic cytotoxicity with 2'-deoxy-5-azacytidine and topotecan in vitro and in vivo. 137 5

2'-Deoxy-5-azacytidine (5-aza-CdR) and cisplatin interact to produce synergistic cytotoxicity against many human tumor cell lines. Preliminary experiments designed to explore the mechanism of this synergy suggested a poor correlation between synergy and the degree of genomic hypomethylation measured following exposure to 5-aza-CdR. Subsequent studies using plasmid DNA suggested that rather than DNA hypomethylation, incorporation of 5-aza-CdR into DNA mediated increased cisplatin binding to DNA and could therefore be essential to the synergistic interaction between these two agents. In this series of experiments, we evaluated the degree of synergy with cisplatin produced against two human melanoma cell lines by two additional antimetabolites that were chosen on the basis of their biochemical properties. In addition, we investigated the synergy between 5-aza-CdR and cisplatin in parental and 5-aza-CdR-resistant murine cell lines, which differed in their sensitivity to 5-aza-CdR and DNA methylation status but incorporated similar amounts of 5-aza-CdR into DNA when exposed to this antimetabolite. In the studies testing additional antimetabolites, cytosine arabinoside, which is incorporated into DNA but does not hypomethylate it, produced synergy with cisplatin that was similar or superior to that obtained using 5-aza-CdR. With 3-deaza-adenosine, which is not incorporated into DNA but produces DNA hypomethylation through inhibition of S-adenosylhomocysteine hydrolase, a primarily antagonistic interaction was observed in the two cell lines studied. In the 5-aza-CdR-sensitive and -resistant cell lines, a very similar synergistic interaction was documented for 5-aza-CdR and cisplatin despite the significant difference observed in DNA methylation levels. Taken as a whole, these data suggest that DNA hypomethylation was not critical to the synergistic cytotoxicity produced by 5-aza-CdR and cisplatin. This finding suggests additional strategies that could further modulate this interaction.
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PMID:Studies on the mechanism of the synergistic interaction between 2'-deoxy-5-azacytidine and cisplatin. 137 33

The distributions of acidic fibroblast growth factor (aFGF) and basic FGF (bFGF) in extracts of various cultured mammalian cells were determined from their elution profiles on heparin-affinity chromatography, and assay of activity as ability to stimulate DNA synthesis in BALB/c3T3 cells. Only aFGF was found in extracts of mouse melanoma B 16 cell and rat Morris hepatoma cell (MH1C1) lines. Other tumor cell lines established from solid tumors and some normal cells contained bFGF as a main component, but blood tumor cell lines contained no aFGF or bFGF. The FGFs in extracts of solid tumor tissues derived by transplantations of these cultured tumor cells and various normal tissues of mice were also examined. Tumors formed by all cell lines, regardless of whether they produced aFGF, bFGF, or neither, contained bFGF that was probably derived from host cells including capillary endothelial cells, in addition to the tumor-derived aFGF or bFGF, if produced. The content of bFGF, possibly derived from the host, in these tumor tissues was comparable to those of various mouse organs other than thymus, lung, spleen, and testis, which have higher bFGF contents. Tumor tissues derived from cultured cells producing bFGF had relatively higher bFGF contents. Like bFGF, aFGF was distributed almost ubiquitously in normal mouse tissues.
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PMID:Distribution of fibroblast growth factors in cultured tumor cells and their transplants. 137 29

Evidence indicates DNA methylation as a part of the regulatory machinery controlling mammalian gene expression. The human melanoma cell line HA-A expresses low levels of transforming growth factor alpha (TGF-alpha). TGF-alpha mRNA accumulated, however, in response to DNA demethylation induced by a nucleoside analog, 5-azacytidine (5-azaC). The importance of DNA methylation in the TGF-alpha promoter region was examined by a transient transfection assay with luciferase reporter plasmids containing a portion of the TGF-alpha promoter. 5-azaC treatment of HA-A cells before the transfection caused a significant increase in the luciferase activity. Since input plasmids were confirmed to remain unmethylated, DNA demethylation of the TGF-alpha promoter itself does not account for the observed increase in TGF-alpha mRNA. Using an electrophoretic mobility shift assay, enhanced formation of protein-TGF-alpha promoter complex was detected in response to 5-azaC treatment. This 5-azaC-induced complex was shown to contain the transcription factor Sp1 by the following criteria: the protein-DNA complex formed on the TGF-alpha promoter contained immunoreactive Sp1; the mobility of the complex in an electrophoretic mobility shift assay was similar to that formed by recombinant Sp1; and DNase I footprinting analysis demonstrated that the 5-azaC-induced complex produced a footprint on the TGF-alpha promoter identical to that of authentic Sp1. These observations suggest that 5-azaC induces TGF-alpha expression by augmenting the Sp1 activity. However, neither the Sp1 mRNA nor its protein was induced by 5-azaC. These results suggest that in HA-A cells, TGF-alpha expression is down-modulated by DNA methylation. In addition, this process may involve the specific regulation of Sp1 activity without altering the amount of the transcription factor.
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PMID:5-Azacytidine treatment of HA-A melanoma cells induces Sp1 activity and concomitant transforming growth factor alpha expression. 138 Jun 48

We report a flexible strategy for the high level expression of a recombinant human monoclonal antibody (mAb) in Chinese hamster ovary (CHO) cells, initially using COS monkey kidney cell transfections to evaluate rapidly modifications to immunoglobulin (Ig) DNA constructs. Using sequential transfections with two amplifiable markers, we generated CHO cell lines and clones that secrete 80-110 micrograms/10(6) cells/24 hours of a mouse-human chimeric IgG1 kappa mAb. This cellular productivity is considerably greater than most murine hybridomas and transfected myelomas. Our data also demonstrate that genomic kappa sequences can improve mAb expression in COS and CHO cells. As a paradigm, we focused our expression studies on a human chimeric form of 3F8, a murine mAb that binds to ganglioside GD2 on neuroblastoma and melanoma tumor cells.
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PMID:High level expression on a chimeric anti-ganglioside GD2 antibody: genomic kappa sequences improve expression in COS and CHO cells. 138 57

Uveal melanoma is the most frequent primary intraocular tumor. The etiology is unknown. Using neutral DNA polymorphisms on chromosomes 2, 3, and 8, we have detected loss of chromosome 3 alleles in 8 of 13 tumors and multiplication of chromosome 8 alleles in 6 of 11 tumors. No anomalies at a locus on chromosome 2 were found in 10 of 10 tumors. These results confirm and extend previous cytogenetic findings and suggest that a tumor suppressor gene on chromosome 3 and an oncogene on chromosome 8 may be involved in the formation or progression of this tumor.
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PMID:Loss of chromosome 3 alleles and multiplication of chromosome 8 alleles in uveal melanoma. 138 62

After in vitro incubation of melanoma tumour cells Cmel453A with either recombinant interferon gamma (rIFN-gamma) or tumour necrosis factor alpha (rTNF-alpha) a dose-dependent inhibition of cell growth occurred; when both cytokines were added, a synergistic action was observed. Inhibition of DNA synthesis, as measured by [3H] thymidine incorporation, occurred after 6 h of incubation with rIFN-gamma or rTNF-alpha, and this action was potentiated when the two cytokines were applied simultaneously. Within 1 h, the level of c-myc mRNA in tumour cells had already decreased by, respectively, 60% (S.D. 7) and 25% (S.D. 7); the combined addition of the cytokines resulted in a greater reduction of c-myc mRNA than by each cytokine alone. Downregulation of c-myc expression is an early event, occurring hours before the actual inhibition of outgrowth. Thus, in melanoma cells like Cmel with a high constitutive expression of the c-myc oncogene, the antiproliferative action of rIFN-gamma and rTNF-alpha may be mediated by an inhibition of the expression of c-myc.
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PMID:Downmodulation of c-myc expression by interferon gamma and tumour necrosis factor alpha precedes growth arrest in human melanoma cells. 138 76

The growth of Demel human metastatic melanoma cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA) and other nonphorbol tumor promoters including palytoxin and okadaic acid. Using flow cytometry, we have demonstrated that the cells arrested growth in G1 and G2 phases of the cell cycle. Detailed analysis of the kinetics of the growth arrest in unsynchronized cells showed that (a) the growth arrest was transient and peaked 16-20 h following addition of TPA; (b) effects of TPA on cell growth began within 1-2 h after the addition; and (c) cells completed S phase and arrested in G2. In addition, TPA induced a pronounced morphological change, which peaked by 1 h and gradually subsided over 24 h. In populations of cells synchronized in G1 using lovastatin, (a) addition of TPA blocked the onset of DNA synthesis up to the end of G1; (b) the lag between addition of the drug and onset of DNA synthesis was less than 30 min; and (c) addition of TPA at the end of G1 prevented the increased phosphorylation of p34cdc2, as determined by immunoprecipitation. The experiments reported here show that TPA transiently blocked the proliferation of Demel melanoma cells at the G1-S border and in G2, thus preventing cells from progressing through the cell cycle. These experiments suggest that pathways involving protein kinase C interact with and rapidly alter the molecular pathways involving p34cdc2 which regulate the onset of DNA synthesis and the G2-M transition.
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PMID:12-O-tetradecanoylphorbol-13-acetate induces transient cell cycle arrest in G1 and G2 in metastatic melanoma cells: inhibition of phosphorylation of p34cdc2. 139 Mar 35


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