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)

An analogue of human melanin-concentrating hormone (MCH) suitable for radioiodination was designed in which Tyr13 was replaced by Phe and Val19 by Tyr. The resulting monoiodinated [125I] [Phe13,Tyr19]-MCH radioligand was biologically active and led to the discovery of high-affinity binding sites on mouse B16-F1, G4F and G4F-7 melanoma cells. Saturation binding analysis with G4F-7 cells revealed 1090 MCH receptors per cell and a KD of 1.18 x 10(-10) mol/l. Receptors for MCH were also found on rat PC12 phaeochromocytoma cells, human RE melanoma cells and COS-7 cells. Competition binding analyses with other peptides such as alpha-MSH, NPY and PACAP demonstrated that MCH receptor binding is specific. rANF(1-28) was found to be a weak competitor of MCH, indicating topological similarities between MCH and rANF(1-28) when interacting with MCH receptors.
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PMID:Melanin-concentrating hormone binding to mouse melanoma cells in vitro. 786 99

It was shown that radiation effects in tumor cells treated with fast neutrons may be increased by the neutron capture reaction 10B(n, alpha)7Li. The classic approach for macroscopic dosimetry in fast-neutron therapy cannot be applied to the dose in boron neutron capture therapy (BNCT). The effectiveness of BNCT in killing tumor cells depends on the number of 10B atoms delivered to the tumor, the subcellular distribution of 10B and the thermal neutron fluence at the site of the tumor. Monte Carlo calculations of the energy depositions of short-range particles with high LET coming from 10B disintegrations were performed and compared to the observed biological effects. The simulation allows us to study the influence of the localization of intracellular 10B in the nucleus, cytoplasma, plasma membrane or extracellular space. The biological response function which describes the probability of the lethal effect produced by a single particle track through the cell nucleus was found by comparing the calculated microscopic dose distribution spectra for single events with the survival observed experimentally. Calculations for a human melanoma cell population treated as a monolayer in the presence or absence of boron with d(14)+Be neutrons will be demonstrated. Two different boron compounds enriched in 10B were investigated in this study: boric acid (H3 10BO3) and p-dihydroxyboryl phenylalanine (BPA). The study shows that a high fraction of BPA enters the cytoplasm while boric acid was found only in the extracellular space. The computer simulations indicate that BPA yields a higher potential effectiveness for inactivation of melanoma cells than boric acid.
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PMID:Monte Carlo simulation of the biological effects of boron neutron capture irradiation with d(14)+Be neutrons in vitro. 789 65

This paper describes our efforts to study structure-activity relationships, improve the antimetastatic potency, and limit the in vivo enzymatic degradation of YIGSR-NH2, a synthetic peptide from the B1 chain of laminin, which reportedly has potential as an antimetastatic agent. To this end we have synthesized a series of psi (CH2NH) peptide analogs (5-9) of YIGSR-NH2 and a number of peptides in which the Tyr residue was replaced with D-Tyr (1), Phe (2), Phe (p-F) (3), and Phe(p-NH2) (4). All new peptides were assayed in vitro for their ability to promote cell attachment in both B16F10 mouse melanoma cells and HT-1080 human fibrosarcoma cells. On the basis of the in vitro assay results, peptides 3-5, 8, and 9 were tested in vivo for their ability to inhibit tumor metastasis to the lungs in mice that were coinjected in the tail vein with B16F10 melanoma cells and 1 mg of peptide. In summary, of the nine new peptides only the Phe(p-NH2) peptide 4 showed consistent in vitro cell attachment activity, but only low in vivo antimetastatic activity.
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PMID:Synthetic laminin-like peptides and pseudopeptides as potential antimetastatic agents. 793 66

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

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX, approximately 8% by weight) bound via the lysosomally degradable spacer Gly-Phe-Leu-Gly and, in certain cases, also melanocyte-stimulating hormone (MSH, 5-10% by weight) were synthesized with the aim of developing a drug conjugate for site-specific delivery to malignant melanoma. Polymer-bound MSH, like free MSH, was able to stimulate tyrosinase activity in B16F10 cells in vitro, confirming the ability of conjugated hormone to interact with the MSH receptor. Similarly, a 125I-labelled conjugate containing MSH was captured by B16F10 cells in vitro more rapidly than a similar polymer without the targeting moiety. HPMA copolymers containing DOX bound via the lysosomally degradable Gly-Phe-Leu-Gly linkage were cytotoxic to a mouse melanoma cell line (M3 S91) in vitro, the MSH-containing conjugate being more active than that without (although the difference in the ID50 was not significant). When administered intraperitoneally or intravenously to C57BL/6J mice bearing intraperitoneal B16F10 tumours, HPMA copolymers containing DOX linked via this biodegradable spacer (with or without MSH) significantly increased animal survival, the maximum ratio of the mean survival of the test group (T) to that of the untreated control (C) T/C observed (approximately 200) over the dose range 5-20 mg DOX/kg being similar to that seen for free DOX. In contrast, neither polymer conjugates containing DOX bound via a non-degradable linkage (Gly-Gly) nor free MSH showed antitumour activity. In mice bearing established subcutaneous B16F10 tumours, biodegradable polymer-bound DOX conjugates given intraperitoneally were more effective than free DOX (which was virtually inactive in this system); conjugates containing MSH were significantly more effective than those without, the maximum T/C being approximately 148 and 324 respectively. Preliminary pharmacokinetic experiments showed evidence of selective MSH targeting of polymer conjugates to subcutaneous B16F10.
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PMID:Polymeric drug-carriers containing doxorubicin and melanocyte-stimulating hormone: in vitro and in vivo evaluation against murine melanoma. 806 63

Six alpha-MSH(4-10) [Nle-Asp-His-D-Phe-Arg-Trp-Lys-amide] derivatives carrying 2 or 1 or no 2,3-dihydroxy-(2S)-propyl (DHP) groups on the Lys10 amino side chain were coupled to diethylene-triaminopentaacetic acid (DTPA, a chelator for 111In) in monomeric and dimeric forms and tested for their binding activity and bioactivity in vitro with mouse and human melanoma cell lines and by receptor autoradiography to tumor sections, as well as in vivo with normal and melanoma-bearing mice: DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10),DTPA-[Nle4, Asp5, D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10), DTPA[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10), DTPA-bis-([Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10)), DTPA-bis[([Nle4,Asp5,D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10)) and DTPA-bis-([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)). In the receptor-binding assays with B16-F1 mouse and D10 human melanoma cells, the KD values ranged between 0.76 and 31.17 nM and in the melanin bioassay the results were similar (EC50 values between 0.15 and 4.40 nM). The tissue distribution of the 111In-labeled compounds in C57Bl/6J mice showed that the dimeric [111In]-DTPA-bis([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)) and the monomeric [111In]-DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10) exhibited the lowest non-specific binding. In mice carrying B16-F1 melanoma tumors, the monomeric compound displayed 2-fold higher 111In uptake by the tumor and a much lower non-specific uptake by the liver (12-fold) and the kidneys (2.5-fold) than the dimeric derivative. This demonstrates that modification of the Lys10 side chain by DHP is a promising lead for new MSH radiopharmaceuticals for melanoma targeting.
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PMID:[111In]-DTPA-labeled analogues of alpha-melanocyte-stimulating hormone for melanoma targeting: receptor binding in vitro and in vivo. 807 62

B16 melanoma sublines (B16-F10-BL6 and B16-F1) exhibited elevated adenosine 3',5'-cyclic monophosphate (cAMP) levels when cultured in Dulbecco's modified Eagle's medium (DMEM) in comparison to cells in RPMI-1640 medium. In parallel, cells cultured in DMEM had increased tyrosinase activity, melanization and dendrite formation, all markers of melanoma differentiation. Also, the proliferative rates of both cell lines were decreased by 80-85% when cultured in DMEM relative to cells maintained in RPMI-1640 medium. In these studies, elevated levels of the melanin precursors tyrosine (Tyr) and phenylalanine (Phe) found in DMEM were shown not to be solely responsible for the phenotypic changes observed with DMEM. Both BL6 and B16-F1 cell lines formed more experimental pulmonary tumor metastasis in syngeneic C57BL/6 mice when maintained in DMEM vs RPMI-1640 medium. Analysis of metastasis formation in nude mice with normal and depleted natural killer (NK) cell activity revealed that the enhanced lung colonizing capacity of the BL6 cells maintained in DMEM was independent of the function of T-cell or NK-cell-mediated immunity. A close association between metastatic ability of tested lines and the expression of the membrane-associated enzyme gamma-glutamyltranspeptidase (gamma-GTPase, EC 2.3.2.2) was observed. The highly metastatic BL6 cell line had 20-fold higher levels of gamma-GTPase activity than the weakly metastatic B16-F1 cell line. Both cell lines, when grown in DMEM, had elevated gamma-GTPase activity that paralleled augmentation of metastatic ability. The dramatic changes in lung-colonizing capacity of the variant B16 melanoma cells maintained in DMEM in contrast to those grown in RPMI-1640 medium may serve as a useful model in understanding certain steps involved in triggering cell differentiation as well as metastasis development.
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PMID:Enhancement of pulmonary metastasis formation and gamma-glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro. 809 41

The role of alkylation of the N3 position of adenine in the cytotoxicity of alkylating agents in mammalian cells is still undefined. By co-transfecting NIH3T3 murine fibroblast and murine B78 H1 melanoma cells with pSG5tag and pSV2neo, we obtained clones expressing the mRNA of the bacterial tag gene coding for N3-methyladenine-DNA glycosylase I (Gly I), which specifically repairs N3-methyladenine. The levels of Gly I were 400 times higher in NIH3T3 pSG5tag (clone 3.9.4) and 12-33 times higher in B78 H1 tag clones (2A4, 2A6, 2C3 and 2D1) than in the respective control cells. The sensitivity to alkylating agents was evaluated in tag-expressing cells in comparison with pSG5, pSV2neo co-transfected control cells. As regards the cytotoxic activity of methylating agents (N-methylnitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, dimethylsulfate and temozolomide) and other alkylators with different structure and different interactions with DNA such as CC-1065 and FCE-24517 (minor groove binders known to bind to N3 of adenine), 4-[bis(2-chloroethyl)amino]-L-phenylalanine and cis-diamminedichloroplatinum II, cytotoxicity was the same for tag-expressing and non-expressing cells. These results suggest that the increased expression of N3-methyladenine-DNA glycosylase is not necessarily a crucial mechanism for the resistance of cells to alkylating agents.
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PMID:3T3 NIH murine fibroblasts and B78 murine melanoma cells expressing the Escherichia coli N3-methyladenine-DNA glycosylase I do not become resistant to alkylating agents. 811 39

B-16 mouse melanoma melanosomes contain two forms of tyrosinase that can be resolved by SDS/PAGE. These forms interact to different extents with the ion-exchanger DEAE-Sephadex and with hydroxyapatite, and have different affinity for the melanosomal membrane and/or the intraorganular matrix. After partial purification and complete separation of the two tyrosinases, several kinetic parameters were analyzed. The form of lower electrophoretic mobility displayed a higher Km for 3,4-dihydroxy-L-phenylalanine (L-dopa) and L-tyrosine, an absolute requirement for the cofactor L-dopa in its tyrosine hydroxylase activity, and a lower ratio of tyrosine hydroxylation to Dopa oxidation. The form of higher electrophoretic mobility displayed lower values of Km for both substrates and was able to exhibit tyrosine hydroxylase activity after a lag period even in the absence of L-dopa. Both forms were stereospecific for the L isomers and sensitive to the specific tyrosinase inhibitor 2-phenylthiourea. These forms do not appear to result from different degrees of glycosylation, nor from limited proteolysis and are also present in the microsomal fraction of B16 mouse melanoma. They might correspond to different gene products, most likely derived from the b and c loci.
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PMID:Tyrosinase isoenzymes in mammalian melanocytes. 1. Biochemical characterization of two melanosomal tyrosinases from B16 mouse melanoma. 822 98

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


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