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)

We investigated Plasmodium falciparum parasitized erythrocyte binding to proteolytic fragments of thrombospondin and the effects of anti-thrombospondin monoclonal antibodies on this binding. Purified human platelet thrombospondin was cleaved by trypsin, chymotrypsin or thrombin. Fragments were separated by heparin-agarose affinity chromatography, removing the amino-terminal heparin-binding region. Trypsin at 5.0 micrograms ml-1 of thrombospondin cleaved thrombospondin to reduced 140 and 120 kDa fragments plus a reduced 25-kDa heparin-binding fragment. Infected erythrocytes bound to intact thrombospondin (3420 +/- 460 infected erythrocytes mm-2) and the carboxy-terminal fragment, yielding 120-140-kDa fragments on sulfhydryl reduction, but not to the 25-kDa fragment (144 +/- 104 infected erythrocytes mm-2 (mean +/- s.d., N = 4). Similar results were obtained with chymotrypsin and thrombin cleavage. When the anti-thrombospondin monoclonal antibody MA-I was added to immobilized thrombospondin prior to infected erythrocytes, adherence was inhibited by 99%. At the same concentration, MA-I inhibited adherence to C32 melanoma cells by only 35%. MA-I binds to a calcium-dependent structure at the C-terminal globular region of thrombospondin. Monoclonal antibody MA-II inhibited adherence to thrombospondin by 46%, while MA-III had no effect. These antibodies bind to the N-terminal globular region which includes the heparin-binding site and the segment connecting the two globular regions, respectively. The site(s) for infected erythrocyte binding on thrombospondin reside in the large, 140- or 120-kDa, proteolytic cleavage fragments, and not in the N-terminal heparin-binding region.
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PMID:Falciparum malaria parasitized erythrocytes bind to a carboxy-terminal thrombospondin fragment and not the amino-terminal heparin-binding region. 219 22

In the previous study, we generated a monoclonal antibody, 8F11, against NL-17, a high metastatic clone derived from a metastatic variant of murine colon adenocarcinoma 26. 8F11 inhibited platelet aggregation induced by NL-17 and recognized a Mr 44,000 membrane protein as antigen. In the present study, the reactivity of 8F11 to murine B16 melanoma and its metastatic variants was examined, and the antigen recognized by 8F11 on the cell surface was characterized. 8F11 was found to strongly react with 3 metastatic variants of B16 melanoma. In contrast, only slight reactivity was observed with parent B16 melanoma. The reactivity of the antibody to these cells was in the order B16F10 greater than B16BL-6 greater than B16F1 much greater than B16. Western blot analysis showed a Mr 41,000 protein as the antigen recognized by 8F11 on the cell surface of B16F10 cells. The Mr 41,000 antigen appeared to be a glycoprotein that bound to wheat germ agglutinin as has been observed for the Mr 44,000 antigen of NL-17. To elucidate the functional role of the Mr 41,000 antigen in B16 melanoma, platelet aggregation induced by B16 and B16F10 was compared. B16 was reported to stimulate platelet aggregation by the generation of thrombin, whereas B16F10 was found to activate platelet by at least 2 mechanisms: one dependent on thrombin and the other independent on thrombin. The activity of B16 and its metastatic variants to induce platelet aggregation in the presence of MD805, a synthetic antagonist of thrombin, well correlated with the reactivity of 8F11 to these cells. 8F11 blocked platelet activation by B16F10 under conditions preventing thrombin activity such as enzymatic formation of lysolecithin through the treatment of the cell surface with phospholipase A2 or in the presence of MD805. These data indicate that Mr 41,000 glycoprotein recognized by 8F11 on metastatic variants of B16 melanoma is involved in the thrombin-independent platelet aggregation. A positive correlation was observed between the levels of Mr 41,000 glycoprotein expression of B16 and its metastatic variants and their pulmonary metastasis after i.v. injection, suggesting Mr 41,000 glycoprotein, as well as other factors reported previously, may play an important role in the hematogenous spread of B16 melanoma.
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PMID:Expression of a Mr 41,000 glycoprotein associated with thrombin-independent platelet aggregation in high metastatic variants of murine B16 melanoma. 220 29

Using batroxobin, a thrombin-like enzyme found in snake venom, the effects of defibrinogenation on artificial lung metastasis in mice were studied. The role of natural killer (NK) cells in the inhibitory effects of defibrinogenation on metastasis was also investigated. Artificial lung metastasis experiments were performed by inoculating either B16-F10 cells or B16-BL/6 cells, highly metastatic strains of B16 melanoma cells, into C57BL/6 mice via the tail vein. The administration of batroxobin significantly inhibited lung metastasis, as did NK activity augmented by poly (I).poly (C) were administered, lung metastasis was more markedly inhibited. When NK activity was suppressed by administration of anti-(asialo GM1) antibody, lung metastasis was markedly increased. When batroxobin was administered with anti-(asialo GM1) antibody, no inhibitory effects on lung metastasis, such as those seen with batroxobin alone, were observed. The administration of batroxobin had no effect at all on spleen lymphocyte NK activity. These results indicated that defibrinogenation due to batroxobin inhibits lung metastasis, and these effects depend on NK activity of the host.
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PMID:Antimetastatic effect of defibrinogenation with batroxobin depends on the natural killer activity of host in mice. 232 60

Carbetimer (carboxyimamidate) is a low molecular weight derivative of ethylene/maleic anhydride polymer. This compound has demonstrated antitumor activity against several animal models with a daily x 5 schedule appearing most effective. A phase I clinical study of the daily x 5 schedule repeated every 28 days was therefore performed. Forty-one evaluable patients received 66 evaluable cycles of Carbetimer at daily doses ranging from 100-11,000 mg/m2. Hypercalcemia was the dose limiting toxicity with both patients at the 11,000 mg/m2 daily dose level and one patient who received 6 cycles of drug at the 4200 mg/m2 dose level developing severe hypercalcemia not explained by the underlying malignancy. Mild nausea, concentration and rate dependent arm pain at the site of infusion, proteinuria, and coagulopathy were also seen. Calcium balance studies revealed hypercalciuria, suggesting increased mobilization of calcium rather than renal retention. In vitro coagulation studies revealed concentration dependent prolongation of the partial thromboplastin time and thrombin time. No complete or partial responses were seen. However mixed response or biochemical response (reduction in serum lactic dehydrogenase) were seen in 5 patients with melanoma or renal cancer. Due to unacceptable toxicity at the 11,000 mg/m2 daily dose level, Carbetimer 8500 mg/m2 is the recommended dose for a 5-day treatment schedule every 28 days. Special attention should be directed toward possible activity against melanoma and renal cancer.
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PMID:Phase I trial of a 5-day course of carbetimer. 238 16

Thrombospondin (TSP), a 450-kD multifunctional glycoprotein with a broad tissue distribution, is secreted upon platelet stimulation, binds to the activated platelet surface, and supports platelet aggregation. We have identified and isolated an 88-kd membrane glycoprotein present in platelets, endothelial cells, monocytes, and a variety of human tumor cell lines that is the membrane binding site for TSP. Endogenous platelet TSP binding to thrombin- and ionophore-stimulated human platelets was inhibited in the presence of the monoclonal antibody OKM5. TSP binding to C32 melanoma cells and HT1080 fibrosarcoma cells was specific and also inhibitable with OKM5 Mab. Cell labeling followed by specific immunoprecipitation demonstrated biosynthesis of a single 88-kD glycoprotein. Binding of TSP to the isolated membrane protein was specific and saturable. These studies identify an 88-kD membrane glycoprotein that reacts with the monoclonal antibody, OKM5, and may function as the cellular TSP receptor.
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PMID:Isolation of the thrombospondin membrane receptor. 243 57

Melanoma growth stimulatory activity factor (MGSA) is a polypeptide which was initially isolated from Hs294 human melanoma cells. Its sequence is identical to the deduced amino acid sequence of the human gro cDNA, isolated from a human tumor cell line. MGSA stimulates the proliferation of malignant melanoma cells, but its function for normal cells has not been defined. Here we report that human umbilical vein endothelial cells are capable of synthesizing and secreting MGSA. The expression and secretion of MGSA are strongly induced by factors often involved in inflammation such as IL-1, TNF, LPS and thrombin. The induction of MGSA mRNA is dose and time dependent and is independent of new protein synthesis. This stimulation could be mimicked by TPA, suggesting that the action could be mediated through activation of protein kinase C. Furthermore, addition of MGSA to the endothelial cell cultures induces gro/MGSA gene expression, implying that an autocrine mechanism exists. Our data suggest that the protein encoded by gro/MGSA mRNA may play a role in inflammation and exert its effects on endothelial cells in an autocrine fashion.
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PMID:Expression and secretion of gro/MGSA by stimulated human endothelial cells. 267 May 60

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
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PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27

Involvement of platelet membrane glycoproteins (GP) in interactions between platelets and tumor cells was studied by using two human tumor cell lines and two monoclonal antibodies against platelet membrane GP. HMV-I cells derived from vaginal melanoma induced platelet aggregation in heparinized plasma, which was not followed by coagulation. M7609 cells derived from colon adenocarcinoma also induced platelet aggregation in heparinized plasma, which, on the contrary, was followed by coagulation. Aggregating activities of the HMV-I cells were abolished by pretreatment with neuraminidase or trypsin, but M7609 activity was not labile to these enzymes. Aggregations induced by M7609 were inhibited by hirudin or MD805, while those by HMV-I were not. M7609 cells dose dependently shortened the recalcification time of normal as well as Factor IX-deficient plasmas, while they were not effective in shortening the time of Factor II- or Factor VII-deficient plasmas. The procoagulant activity of HMV-I cells was 1000 times less than M7609 on the basis of cell numbers. When human platelets were preincubated with monoclonal anti-GPIb or anti-GPIIb/IIIa complex antibodies, neither cell line could cause aggregations. These findings suggest that both GPIb and the GPIIb/IIIa complex on the platelet surface are involved in the thrombin-dependent and -independent platelet aggregations induced by tumor cells.
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PMID:Involvement of platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa complex in thrombin-dependent and -independent platelet aggregations induced by tumor cells. 291 Apr 73

An inhibitor of plasminogen activator (PA) secreted by a tumorigenic, but non-metastatic, rat mammary adenocarcinoma cell line has been purified to apparent homogeneity and characterized. It strongly inhibited human urokinase, but was 100 times less potent in inhibiting bovine trypsin and had no effect on plasmin or thrombin. A secreted, urokinase-type PA (Mr 48 000) and a cell-associated PA from a metastatic rat adenocarcinoma cell line were also strongly inhibited. In contrast, a tissue-type PA (Mr 66 000), secreted by human melanoma cells, was only slightly inhibited. Purified inhibitor showed a band of Mr 66 000 in sodium dodecyl sulphate/polyacrylamide gel electrophoresis and an isoelectric point of 4.5 after chromatofocusing. The inhibition of human urokinase was non-competitive.
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PMID:Purification and characterization of an inhibitor of plasminogen activator released by rat mammary adenocarcinoma cells. 308 43

Peptide aldehyde transition state analogue inhibitors of serine and cysteine proteases have been used to selectively inhibit proteases for which prior evidence supports a role in tumor cell metastasis. These enzymes include cathepsin B, urokinase plasminogen activator (PA), and thrombin. The inhibition constants of the peptidyl aldehyde inhibitors show that they are highly selective for a particular targeted serine or cysteine protease. The inhibitors are introduced by i.p. injection or by miniosmotic pumps into syngeneic C57BL/6 mice also given injections of B16-F10 melanoma cells, and the number of metastatic foci in the lung was determined. While the injection protocol gave an initially high but changing in vivo concentration of inhibitor over time, the minipump implant gave a constant steady state concentration of inhibitor over 5-7 days. Minipump infusion of leupeptin (acetylleucylleucylargininal), a strong inhibitor of cathepsin B at a steady state plasma concentration 1000-fold greater than its Ki(cathepsin B), gave no significant decrease in lung colonization by the B16 tumor cells. Ep475, a stoichiometric irreversible peptide inhibitor of cathepsin B-like proteases, also did not significantly inhibit metastatic foci formation. Introduction of selective inhibitors of urokinase PA, tert-butyloxycarbonylglutamylglycyl-argininal and H-glutamylglycylargininal at concentrations near its Ki, produced no significant decrease in mouse lung colonization. The selective thrombin inhibitor D-phenylalanylprolylargininal infused to a steady state concentration 100-fold greater than its Ki dramatically increased B16 melanoma colonization of mouse lung. The results indicate that neither secreted cathepsin B-like nor urokinase PA have roles in B16 colonization of mouse lung, while thrombin may have a role in preventing metastasis. These experiments do not eliminate roles for a cathepsin B-like enzyme or urokinase PA in the initial steps of the metastatic process.
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PMID:Selective inhibition of proteolytic enzymes in an in vivo mouse model for experimental metastasis. 308 87


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