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 new platelet aggregation inhibitor compound, 5-(2-chlorobenzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrochloride (ticlopidine), was examined for its inhibitory effects on blood-borne metastasis using three different rodent tumors (B16 melanoma, Lewis lung carcinoma, and rat ascites hepatoma, AH130). Ticlopidine was administered p.o. to the rodents. It inhibited the aggregation of platelets induced by adenosine diphosphate, thrombin, crude extract of AH130, and viable AH130 and B16 melanoma cells and also resulted in a significant decrease of pulmonary metastasis induced by i.v. injection of B16 melanoma and AH130. Spontaneous pulmonary metastasis of Lewis lung carcinoma was also inhibited by p.o. administration of ticlopidine. This new compound may be a useful agent for inhibiting platelet aggregation caused by various agents and for suppressing hematogenous pulmonary metastasis.
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PMID:Effects of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Ticlopidine), a platelet aggregation inhibitor, on blood-borne metastasis. 730 88

The surface glycoprotein CD36 (GPIV) is known to mediate the adhesion of Plasmodium falciparum malaria-infected red blood cells and to be a receptor for extracellular matrix proteins such as collagen and thrombospondin. The murine monoclonal IgM antibody NL07, which is specific for CD36, has now been shown to also be a potent inhibitor of the adhesion of P falciparum malaria-infected red blood cells to C32 melanoma cells. Treatment of platelets with NL07 monoclonal antibody resulted in rapid degranulation, release of ATP and serotonin, increase in [Ca2+]i, and tyrosine phosphorylation of a substrate protein of 130 kD. In about one-half of the experiments, activation with NL07 resulted in the formation of small aggregates of 10 to 30 platelets, whereas in the other half of the experiments, large aggregates were seen similar to those induced by adenosine diphosphate (ADP) and these large aggregates could be converted to the small aggregates by ATP alpha S or by AP-2 or other antibodies against GPIIb and/or IIIa. Microaggregates of 2 to 5 platelets were seen with Glanzmann's platelets that constitutively lack GPIIb/IIIa. Aggregate formation was not seen with heat-treated serum, in the presence of anti C1q antibodies, or when using C5-, C8-, or C9-deficient human sera. Although activation of platelets with purified complement components results in a slow morphologic change without aggregation, involvement of CD36 results in rapid complement-mediated activation leading to formation of small aggregates that is largely independent of GPIIb/IIIa and that, under certain circumstances, proceeds to the formation of large ADP-dependent aggregates.
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PMID:Platelet activation and inhibition of malarial cytoadherence by the anti-CD36 IgM monoclonal antibody NL07. 750 21

In this study we have investigated, using three different human melanoma cell lines (M1Do., M3Da., M4Be.). the varying capacity of melanoma cells to induce platelet aggregation in the presence or absence of inhibitors of ADP or thrombin. The expression levels of different integrins (alpha v, beta 3, alpha v beta 3, alpha IIb, alpha v beta 3) were evaluated by immunoprecipitation, binding and flow cytometry studies. The level of ADP in supernatants of melanoma cells were quantified by ADP bioassay and HPLC. Platelets were irreversibly aggregated by M3Da, as shown by electron microscopy, in contrast to M1Do, which induced a slow reversible aggregation. M4Be. did not induce platelet aggregation. In both cases, with M3Da. or M1Do., apyrase but not PPACK inhibited platelet induced aggregation. An anti-alpha v beta 3 monoclonal antibody (LYP18) or polyclonal antibody inhibited platelet aggregation. A similar number of LYP18 molecules bound to the surface of M1Do., M3Da. and M4Be. cell lines. Biological HPLC assays of ADP present in the supernatant of tumour cell lines showed the highest concentration of ADP to be secreted by M3Da., followed by M1Do., and none detected for M4Be. These results show that differences in in vitro aggregating potential of the three human melanoma cell lines are not related to low integrin expression levels but to their ability to generate ADP. Generation of ADP by human melanoma cells may act as important modulator of melanoma-platelet interactions.
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PMID:Human melanoma cell lines differ in their capacity to release ADP and aggregate platelets. 752 41

Four disintegrins, eristostatin, albolabrin, barbourin and echistatin, injected IV into C57BL/6 mice in combination with B16F10 murine melanoma cells, inhibited formation of experimental lung metastases with ID50s of 0.05, 1.0, 0.9, and 3.7 mumoles per mouse, respectively. When injected 1 h after tumor cells, albolabrin, echistatin and barbourin had the same antimetastatic activity, while eristostatin was not active. Eristostatin (IC50 7-8 nM) was more potent than echistatin (IC50 74-75 nM), barbourin (IC50 46-60 nM), and albolabrin (IC50 130-165 nM) as an inhibitor of murine platelet aggregation induced by ADP or tumor cells. Fibronectin was the best substrate for melanoma cell adhesion (95%), followed by laminin (47%) and vitronectin (24%). Albolabrin was the strongest and eristostatin the weakest inhibitor of cell adhesion to all substrata. Adhesion of melanoma cells to albolabrin, echistatin, and barbourin was partially inhibited by monoclonal antibody against mouse alpha v subunit. This antibody bound to B16F10 melanoma cells in suspension and inhibited binding of fluorescein isothiocyanate (FITC)-labeled disintegrins to these cells, being the most effective with FITC-labeled albolabrin. Our study suggests that a major contribution of eristostatin to inhibition of lung colonization is via preferential binding to platelet alpha IIb beta 3 integrin and blocking tumor cells interaction with platelets. A major contribution of albolabrin, barbourin and echistatin appears to be by interference with other integrin receptors on the tumor cell surface. Albolabrin appeared to inhibit RGD-dependent integrins containing alpha v subunit, such as alpha v beta 3 and alpha v beta 1.
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PMID:Effect of four disintegrins on the adhesive and metastatic properties of B16F10 melanoma cells in a murine model. 754 46

Modulation of cytoplasmic Ca++ concentration is a mechanism common to signal transduction pathways regulating many cellular phenomena, including the interactions of tumors with the hemostatic system. We have investigated the pro-aggregating and pro-coagulant activities of human tumor cell lines cultured in vitro and the ability of different platelet agonists to induce Ca++ transients in these cells. Cells of a malignant mesothelioma line activated platelets by a thrombin-dependent mechanism; on the contrary, HeLa cells, derived from a uterine cervical cancer, possessed ADP-dependent pro-aggregating activity, and DND-IA melanoma cells did not stimulate platelet aggregation. All cell lines showed a tissue-factor-like procoagulant property, more pronounced in mesothelioma cells. Furthermore, ADP was able to induce a transient increase in cytoplasmic Ca++ concentration in tumor cells from all lines; collagen showed this effect in mesothelioma cells and in HeLa cells, and thrombin was effective only in mesothelioma cells. PAF never induced Ca++ fluxes in any of the cell lines investigated. Finally, the calcium-channel blocker verapamil inhibited agonist-induced Ca++ transients in tumor cells and in vitro tumor-cell growth. These data may help to identify new possible mechanisms of the 2-way interaction of tumors with the hemostatic system.
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PMID:Effect of different platelet agonists on intracellular free Ca++ concentrations in human tumor cells: possible role in tumor growth. 762 70

Synthetic peptides related to amino acid residues 29-42 of human serum amyloid A (SAA), Tyr-Ile-Gly-Ser-Asp-Lys-Tyr-Phe-His-Ala-Arg-Gly-Asn-Tyr, were found to inhibit the adhesion of human T-lymphocytes and of mouse M4 melanoma cells to surfaces coated with the major cell adhesive glycoproteins of the extracellular matrix, laminin or fibronectin. Correspondingly inhibitory activity was manifested by the entire 14-residue peptide, by its YIGSD laminin-related domain, and by RGN, the fibronectin-related domain. Intact recombinant SAA (rSAA) and its 1-76 fragment, an amyloid A (AA) protein, also inhibited cell adhesion. The peptides did not inhibit collagen and ADP-induced aggregation of human platelets. Proteolysis of SAA by lysosomal enzymes originating from human neutrophils led to generation of specific peptide segments some of which pertain to the 29-42 domain. It is suggested that the acute-phase protein SAA might be involved, either directly or via its peptide fragments, in inhibition of inflammatory reactions or metastatic processes which depend on integrin and possibly other extracellular-matrix-specific receptors mediated specific recognition and interactions with immobilized components of blood-vessel walls.
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PMID:Inhibition of cell adhesion to glycoproteins of the extracellular matrix by peptides corresponding to serum amyloid A. Toward understanding the physiological role of an enigmatic protein. 803 6

In this study, we examined the effect of triflavin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, on human cervical carcinoma (HeLa) cell- and B16-F10 mouse melanoma cell-induced platelet aggregation (TCIPA) in heparinized platelet-rich plasma. TCIPA appears to play an important role in the development of certain experimental tumor metastases. Two ADP-scavenging agents, apyrase (10 U/ml) and creatine phosphate (CP) (5 mM)/creatine phosphokinase (CPK) (5 U/ml) completely inhibited B16-F10 TCIPA, but hirudin (5 U/ml) had no effect. In contrast, apyrase and CP/CPK did not inhibit HeLa TCIPA while hirudin completely inhibited it. Furthermore, HeLa cells initially induced platelet aggregation and then blood coagulation at a later stage. In addition, HeLa cells shortened, in a concentration-dependent manner, the recalcification time of normal as well as factor VIII- and IX-deficient human plasma, but did not affect the recalcification time of factor VII-deficient plasma. This suggests that HeLa TCIPA occurs via activation of the extrinsic pathway, probably owing to tumor cell expression of tissue factor-like activity. HeLa cell-induced thrombin generation was confirmed by detection of amidolytic activity towards a chromogenic substrate, S-2238 (H-D-Phe-Pip-Arg-p-NA). Triflavin and GRGDS inhibited, in a dose-dependent manner, TCIPA caused by either cell line. On a molar basis, triflavin was 10,000-30,000 times more potent than GRGDS in this regard. Moreover, monoclonal antibodies raised against glycoprotein (GP) IIb/IIIa complex (i.e., 7E3 and AP2) and against GP Ib (i.e., AP1) completely inhibited HeLa TCIPA. 7E3 and AP2 inhibited B16-F10 TCIPA by up to 80% whereas AP1 showed only 30% inhibition of B16-F10 TCIPA. In conclusion, the inhibitory effect of triflavin on HeLa and B16-F10 TCIPA may be mediated principally by the binding of triflavin to the fibrinogen receptor associated with GP IIb/IIIa complex on the platelet surface. However, GP Ib is also involved in HeLa TCIPA as thrombin formation is the key factor in triggering platelet aggregation caused by HeLa cells.
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PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits tumor cell-induced platelet aggregation. 822 81

Platelet function in 16 patients with metastatic renal cell carcinoma and melanoma was studied sequentially over the first 96 hr of treatment with moderate and high-dose interleukin-2 (IL-2). During the first 96 hr of therapy, an increased ex vivo platelet maximal aggregation (MA) response to ADP, epinephrine, and arachidonic acid was paralleled by a decrease in the peripheral platelet count. Plasma specimens from patients receiving the moderate dose schedule showed a significant IL-2 induced secretory response of the platelet alpha-granule components beta-thromboglobulin (BTG) and platelet factor 4 (PF4) and the eicosanoid thromboxane B2 (TBX2) as measured by RIA. The increase in TXB2 was highly correlated with MA when analyzed by bivariate regression analysis, whereas the addition of PF4 to TXB2 in a multiple regression analysis further increased their correlation to MA. The observed decrease in peripheral platelet count correlated significantly with MA and PF4 secretion. High-dose IL-2-treated patients showed a statistically significant increase in the percentage of large platelets exceeding 12 fl in diameter and platelet responsiveness to hypotonic shock. These observations suggest that IL-2 therapy results in a reduced peripheral platelet pool, with an increased proportion of the remaining pool of platelets larger, more viable, and activated.
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PMID:Effects of interleukin-2 administration on platelet function in cancer patients. 829 93

Low-molecular-mass Arg-Gly-Asp (RGD)-containing polypeptides were isolated from the venom of Trimeresurus elegans by a simple two-step procedure consisting of membrane filtration and reverse-phase HPLC. A combination of electrospray MS, fast-atom bombardment MS and Edman degradation allowed us to ascertain the presence in the venom of different isoforms and to determine their primary structures. The amino acid sequences resembled the structure of elegantin, the only disintegrin previously reported from the T. elegans venom [Williams, Rucinski, Holt and Niewiarowski (1990) Biochim. Biophys, Acta 1039, 81-89]. MS analyses indicated the occurrence of differential proteolytic processing at both the N-terminus and the C-termins of the polypeptide chains. The amino acid sequence alignment of the elegantin isoforms with known components of the disintegrin family demonstrated the complete conservation of the 12 cysteine residues involved in disulphide bridges. Molecular modelling of elegantins predicted an overall folding of these molecules quite similar to that reported for the kistrin solution structure. The newly identified polypeptide isoforms strongly inhibited ADP-induced aggregation in both human and canine platelet-rich plasma but showed a different species-dependent specificity. These molecules were also able to inhibit B16-BL6 murine melanoma cell adhesion to immobilized fibronectin. The comparison of the structures and biological activities of elegantin isoforms and kistrin allowed us to highlight some structural features that, in addition to the RGD locus might be involved in the interaction of these snake-venom polypeptides with the integrin receptors on the platelet and cell surface.
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PMID:Amino acid sequence and molecular modelling of glycoprotein IIb-IIIa and fibronectin receptor iso-antagonists from Trimeresurus elegans venom. 892 Sep 80

The pineal hormone melatonin modulates constitutive protein secretion from murine melanoma M2R cells in vitro, in a cholera-toxin (CTX)-sensitive process, without effecting major changes in cAMP. The effects of melatonin on GTP binding proteins and putative CTX substrates in these cells were investigated. Melatonin enhanced GTP gamma 35S binding and the incorporation of 32P-P3-(4-azidoanilido)-P1-5'-guanosine triphosphate (Az-32P-GTP) into 94, 40 and 28 kilodalton proteins. Similar changes were induced by CTX treatment. In addition, melatonin enhanced ADP ribosylation of several proteins, among them 94 and 40 kilodalton bands, apparently at arginyl residues. CTX catalyzed the ADP ribosylation of 45 and 40 (both recognized by antibodies specific to the C-terminal peptide of the Gs alpha subunit) and 94 kilodalton proteins and attenuated melatonin's effect. The melatonin-mediated ADP ribosylation reactions were attenuated by nicotinamide which inhibits mono(ADP ribosyl)transferases and poly(ADP-ribose)synthetase, but not by 3-amino benzamide, a specific inhibitor of poly(ADP-ribose)synthetase. Nicotinamide but not 3-amino benzamide prevented the enhancement by melatonin of GTP gamma 35S binding. These results indicate that melatonin enhances protein ADP ribosylation and consequently GTP exchange in a number of CTX-sensitive G proteins. They demonstrate a novel route for concerted activation of multiple GTP binding proteins by a single hormone.
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PMID:Enhancement by melatonin of GTP exchange and ADP ribosylation reactions. 896 Dec 51


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