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)

Transplantable mouse melanomas possess a melanotropin-sensitive adenylate cyclase system which is responsive to alpha-melanotropin, beta-melanotropin, adrenocorticotropin (ACTH) and prostaglandin E1. It was found that sensitivity to ACTH was not directed towards the ACTH activity but to the intrinsic melanotropin activity of the ACTH molecule. Therefore, the melanotropin-sensitive adenylate cyclase system is hormonally specific to the intrinsic melanotropin activity of peptide hormones and is unique in the melanoma tissue. The significance of the sensitivity to prostaglandin E1 is obscure at present. The melanotropin-sensitive adenylate cyclase requires the presence of Mg2+ or Mn2+, for its enzymic activity. Ca2+ inhibit the enzyme in the presence of a wide range of concentrations of Mg2+. The enzymic activity is ATP concentration-dependent and the saturation concentration appears to be 1 mM. The enzyme is very labile in the unfractionated tumor homogenates. A washed 11000 X g particulate fraction, representing about 30-60% of the total enzymic activity, was found to be more stable and could be stored at 5 degrees C for 2 h without appreciable loss of the activity. This fraction retained sensitivity to melanotropin, prostaglandin E1 and NaF. About 20% of the activity of the tumor homogenate could not be sedimented by centrifugation at 105000 X g for 60 min. This "soluble" fraction was not responsive to melanotropin, prostaglandin E1 and NaF and might be a degradative product produced by the fractionation. Cyclic AMP and alpha-melanotropin were able to increase the tyrosinase activity of isolated mouse melanoma-cells in vitro under the same conditions.
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PMID:PHrmonal specificity of the melanotropin-sensitive adenylate cyclase of mouse melanoma and effect of cyclic AMP on the tyrosinase activity of mouse melanoma cells, in vitro. 0 31

The dose-survival curve of cultured melanoma cells was changed by post-irradiation treatment with 2,4-dinitrophenol (DNP). The parameters of the curves were Do = 147 R and n = 5 . 6 for untreated cells and Do = 143 R, n = 7 . 9 and Do = 142 R, n = 2 . 0 for the cells treated with 10(-5) M DNP and 5 x 10(-5) M DNP in phosphate-buffered saline, respectively. The content of ATP in the cell decreased to 5% of the control level after treatment with either concentration of DNP. The recovery of ATP content was rapid and complete after 2 hours' incubation in culture medium after the removal of 10(-5) M DNP, but was retarded and incomplete after 4 hours with 5 x 10(-5) M DNP. Thus prolonged ATP deprivation with a high concentration of DNP results in an inhibition of recovery and a reduction in the n-value.
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PMID:Alterations in the survival of X-irradiated cells by 2,4-dinitrophenol depending on ATP deprivation. 31 76

External ATP causes a remarkable change in the passive permeability of the plasma membrane in several types of transformed cells. When mouse melanoma cells, Clone-M3, were exposed to ATP in Tris-buffered saline, a great increase in the passive permeability was induced within several minutes. Longer exposure of Clone-M3 cells to external ATP led to a decrease in cell viability. Similar results were obtained with Ehrlich ascites cells, but none of these ATP effects were noted in untransformed cells such as NIH 3T3 cells or BALB/c mouse embryonic fibroblasts. The in vitro cytotoxic effects of antitumor agents (5-fluorouracil, adriamycin, mitomycin C and nimustine hydrochloride) against Clone-M3 cells were additively potentiated by treatment with external ATP, which also synergistically enhanced the cytotoxicity of vincristine. However, the effects of these drugs on mouse embryonic fibroblasts were not modulated by ATP. These results suggest that ATP-treatment is a useful means of enhancing a selective toxicity for tumor cells.
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PMID:Modulation of membrane permeability, cell proliferation and cytotoxicity of antitumor agents by external ATP in mouse tumor cells. 154 68

To study the mechanisms by which insulin regulates proliferation, we have compared wild-type Cloudman melanoma cells, whose growth in inhibited by insulin (insinh) to variant lines that were genetically selected for resistance to insulin (insres). Scatchard analysis of insulin binding to five insres) lines and six insres variants revealed a marked reduction in the number of high-affinity binding sites for insulin in the insres lines, and insres lines displayed an abnormal beta-subunit of the insulin receptor. During autophosphorylation of the wheat germ agglutinin-purified receptor, the beta-subunit apparently underwent proteolytic degradation. This proteolysis was ATP-dependent and was prevented by bovine pancreatic trypsin inhibitor, and phenylmethylsulphonyl fluoride, but not by aprotinin or leupeptin. Receptor proteolysis was not observed in wild-type lines. The results suggest that insulin resistance in the mutant Cloudman melanoma cells is apparently due to proteolysis of the beta-subunit of insulin receptor which, in turn, alters insulin binding capacity of the cells and blocks their anti-proliferative response to the hormone.
Melanoma Res 1992 Jul
PMID:Defect of insulin receptor in insulin-resistant variants of Cloudman S91 mouse melanoma cells. 164 30

Two phenotypic parameters, aberrant expression of protein kinase C and tumor cell-induced platelet aggregation (PA), have been correlated with abnormal growth behavior and metastatic potential of tumor cells. We recently observed that N,N,N-trimethylsphingosine (TMS) and N,N-dimethylsphingosine (DMS), but not sphingosine (SPN), had an inhibitory effect (via blocking of transmembrane signaling) on the growth of various human tumor cell lines in vitro as well as in vivo in nu/nu mice (K. Endo et al., Cancer Res., 51: 1613-1618, 1991). We therefore investigated the effects of TMS, DMS, and SPN on (a) PA induced by ADP and thrombin; (b) PA induced by melanoma cell line B16/BL6; and (c) experimental lung colonization as well as spontaneous lung metastasis of BL6 cells in syngeneic C57BL/6 mice. In experiments on agonist-induced PA, TMS inhibited PA and ATP secretion 5-fold more strongly than DMS or SPN. This effect may be based on the inhibition of Mr 47,000 platelet protein phosphorylation and/or inhibition of phosphatidylinositol turnover as a transmembrane signaling pathway in platelets. Tumor cell (BL6 melanoma)-induced PA and ATP secretion were also strongly inhibited by TMS, but not by DMS or SPN. Unlike ADP- or thrombin-induced PA, BL6 cell-induced PA was not inhibited by Calphostin-C (a potent protein kinase C inhibitor) or cilostazol (a potent inhibitor of PA based on inhibition of cyclic AMP phosphodiesterase). Since many previous studies suggested that the ability of tumor cells to induce PA is related to the degree of malignancy (e.g., metastatic potential) of tumor cells, we studied the effect of TMS on lung metastatic potential. Three independent sets of experiments, as described below, all showed clear inhibition of lung metastasis by administration of TMS: (a) i.v. coinjection of BL6 melanoma cells and TMS; (b) i.v. injection of TMS and, 1 h later, BL6 cells; (c) spontaneous metastasis to lung from s.c. BL6 tumor (TMS administered after establishment of tumor, followed by resection of tumor). In comparison to tumor growth inhibition produced by TMS or DMS, inhibition of melanoma metastasis by TMS is obvious at lower doses.
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PMID:Cell membrane signaling as target in cancer therapy. II: Inhibitory effect of N,N,N-trimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. 165 77

A novel technique for metabolic imaging using quantitative bioluminescence and single photon imaging was used to measure the distribution of ATP and lactate in two types of human melanoma xenografts with different radiobiologically hypoxic cell fractions (MF: 45 +/- 17% and EE: 6 +/- 3%; mean +/- SD). The tumours were s.c. grown in nude mice and were used for measurement at volumes of 153-3072 mm3. For metabolic imaging the rapidly frozen tumours were serially sectioned, and each cryosection was brought into contact with a frozen bioluminescent enzyme cocktail using a specially designed glass sandwich system. After thawing section and cocktail the luminescence was started, and light was emitted from the section with an intensity that is proportional to the local metabolite concentration. The photons were imaged directly through a microscope and an imaging photon counting system. A clear-cut correlation was documented between the distribution of relatively high ATP concentrations and of viable cell regions. The data obtained showed lower ATP concentrations in the tumour centres compared to the periphery, whereas lactate was inversely distributed within the melanomas. There was a trend towards a decrease in ATP with increasing tumour size in central, but not in peripheral, parts of both melanoma types. The concentration of neither ATP nor lactate measured in corresponding tumour areas showed differences related to the melanoma type. Thus, these two metabolites did not reflect the difference in the radiosensitivity of these tumours.
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PMID:Comparative imaging of structure and metabolites in tumours. 167 63

A major part of the present understanding of the molecular basis of signal transduction has been gained from in vitro studies using classical biochemical methods. In this study, we used 31P NMR spectroscopy to investigate the response of live M2R mouse melanoma cells to stimulation by melanocyte-stimulating hormone (MSH; melanotropin). In the presence of 3-isobutyl-1-methylxanthine and a synergistic dose of forskolin (1.67 microM), MSH induced a transient (approximately 60-min) rise in the cellular concentration of 3',5'-cyclic adenosine monophosphate (cAMP), which coincided in time with an equivalent decrease (approximately 40%) in ATP. However, no detectable change in phosphocreatine concentration was observed. Concomitantly, MSH induced a striking and unexpected increase in the concentration of three phosphomonoester (PME) metabolites (approximately 2-fold increase in total PME signal area); one signal has been assigned to phosphoethanolamine. The levels of the PMEs remained high for 2-4 hr and declined slowly (approximately 10 hr) to basal level, following perfusion with fresh culture medium. The increase in PME was also observed after stimulation with MSH alone. In contrast, stimulation with a high dose of forskolin (50 microM) and isobutylmethylxanthine (0.2 mM), although effective in stimulating the production of cAMP, did not induce the PME response. Evaluation of the cells' energetics indicated that the enhanced production of phosphoethanolamine is probably not due to ethanolamine phosphorylation. Therefore, it is likely to result from hydrolysis of phosphatidylethanolamine by a specific phospholipase C. The response of the PMEs appears to be regulated by a cAMP-independent process, suggesting the existence of an alternative transduction pathway controlled by MSH.
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PMID:Stimulation of cAMP and phosphomonoester production by melanotropin in melanoma cells: 31P NMR studies. 170 40

Activity of replicase complex enzymes involving thymidine kinase (TK), ribonucleotide reductase (RR), DNA-polymerases alpha and beta as well as DNA synthesis and single breaks in DNA were studied during growth of P388 ascites tumor. Under these conditions the rate of DNA synthesis was distinctly decreased via salvage pathway and de novo. Single breaks were not detected in the preexistent DNA within various periods after transplantation of P338 leukemic cells. Retardation of DNA synthesis during tumor growth correlated with a decrease in TK, RR and DNA-polymerase alpha activities, while DNA-polymerase beta activity was markedly increased. Growth of melanoma B16 was accompanied by a decrease in content of ATP, ADP, NAD, phosphocreatine and phosphosaccharides as well as by an increase in the level of inorganic phosphates.
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PMID:[Changes in the replication apparatus and phosphorus-containing metabolite pool in experimental tumors in animals during development]. 181 11

Binding of iodine-125-labeled thrombin to fibrin clots from two siblings with juvenile stroke was 30% of normal, and abnormally high amounts of the radioligand (not adsorbed by fibrin) were found in the supernatant. In concordance with this finding, supernatants from the patients' fibrin clots caused abnormal enhancement of platelet aggregation, ATP secretion, and binding of 125I-fibrinogen to platelets exposed to subthreshold concentrations of ADP or epinephrine. Hirudin suppressed the enhancing effect of the patients' supernatants, and substitution of gamma-thrombin for alpha-thrombin led to normalization of platelet responses. Under some experimental conditions, degradation of the patients' fibrinogen by plasmin was impaired. However, the euglobulin lysis time, the rate of fibrin degradation by plasmin, and the lysis of the patients' plasma clots by human melanoma tissue-type plasminogen activator were normal. Patients' plasmas, as well as purified fibrinogen, showed a prolonged thrombin time (partially corrected by 10 mM CaCl2) and an impaired release of fibrinopeptide A in response to thrombin. However, the release in response to reptilase was normal, and the reptilase, ancrod, and thrombin coagulase times were within control (normal) values. In addition, the patients' fibrinogen showed normal polymerization of preformed fibrin monomers, normal sialic acid content, and normal binding to ADP or epinephrine-stimulated platelets. Our studies support the concept that thrombin and platelets play an important role in the occurrence of stroke in these patients and suggest a direction to be followed to identify the mechanism(s) contributing to thrombosis in subjects with abnormal fibrinopeptide release.
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PMID:A role for platelets and thrombin in the juvenile stroke of two siblings with defective thrombin-adsorbing capacity of fibrin(ogen). 182 31

1,3 Dimethylthiourea (DMTU) has previously been shown by us to inhibit the growth of melanoma cells and to induce phenotypic alterations in these cells, including ultrastructural alterations of mitochondria. These findings raised the possibility that impaired mitochondrial function might be involved in mediating the effect of DMTU on cell growth and phenotypic expression. The present study indicates that DMTU as well as another growth inhibitory methylurea derivative, tetramethylurea (TMU) significantly decrease ATP content in the B16 melanoma cell line. 1,3 Dimethylurea (1,3DMU) and 1,1 dimethylurea (1,1DMU) which are poor growth inhibitors, do not reduce ATP content significantly. Altered energy metabolism in the DMTU-treated cells is reflected by inhibition of the activity of cytochrome c oxidase and by increased lactate levels. A cell line selected for resistance to growth inhibition by DMTU was shown to be completely resistant to induction of phenotypic alterations by DMTU. These cells possess high lactate levels, high ATP content and a somewhat decreased Na/K ATPase activity as compared to wild type B16 F10 cells. 1,3 DMTU treatment of the resistant cells leads to a decrease in the activity of the mitochondrial enzyme cytochrome c oxidase, similar to its effect on the wild type B16 F10 cells. DMTU also reduces ATP content moderately in the resistant cells. However, the levels of ATP do not decrease beyond those found in untreated B16 F10 wild type cells. Taken together the results suggest that decreased ATP content might be involved, at least partially, in mediating the effects of DMTU on B16 melanoma cell growth and phenotypic expression.
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PMID:Dimethylthiourea inhibition of B16 melanoma growth and induction of phenotypic alterations; relationship to ATP levels. 185 Jun 8


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