Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cyclic hexapeptide cyclo(Lys-Gly-Asp-Gln-Leu-Ser-) 10 was synthesized stepwise in solution by acylation of peptide ester trifluoroacetates directly with preactivated Boc-amino acids using the DCC/HOBt method; the final cyclization reaction was performed using the pentafluorophenyl ester method in solution (1-4). This peptide is a cyclic derivative of murine tumor necrosis factor-(127-132) and is designed as a potential antitumor agent. The cyclic peptide 10 displayed weak cytotoxic activity on three of the four human tumor cell lines tested.
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PMID:Synthesis of a cyclic hexapeptide with sequence corresponding to murine tumor necrosis factor-(127-132) as a novel potential antitumor agent. 227 46

The processes of migration and invasion by human tumor cells are likely to involve specific cell surface receptors, such as receptors for the extracellular matrix molecules fibronectin, laminin, and collagen. We have examined the roles of several of these receptors using a set of monoclonal antibodies directed against the beta 1 integrin family, as well as a series of synthetic peptides reported to inhibit various interactions of each of these proteins with the cell surface. The most general inhibitor of tumor cell migration was found to be the anti-beta 1 monoclonal antibody 13, which inhibited the migration of human HT-1080 fibrosarcoma cells, 5637 bladder carcinoma cells, VA13 viral transformants, and HCT 116 colon carcinoma cells when fibronectin was the migration substrate. Moreover, this antibody was particularly effective in blocking cell migration on laminin, as well as migration within 3-dimensional collagen gels. It also inhibited in vitro invasiveness in a reconstituted basement membrane invasion assay (Matrigel assay) at concentrations as low as 1 microgram/ml. Integrins of the beta 1 class thus appear to play a central role in several types of migration by a variety of human tumor cell lines. Anti-alpha 5 fibronectin receptor monoclonal antibody 16 also significantly inhibited migration on fibronectin, but not on other substrates, in 3 of the 4 cell lines. Conversely, anti-alpha 2 monoclonal antibody F17 strikingly inhibited migration in 3-dimensional collagen gels, but not on other substrates, implicating the alpha 2 beta 1 integrin system in migration of tumor cells within collagenous matrices. A series of synthetic peptides previously reported to inhibit interactions of normal cells with fibronectin, laminin, and collagen were also tested as inhibitors of tumor cell migration. Peptides containing the Arg-Gly-Asp adhesive recognition signal were partially inhibitory, but with occasional exceptions, most other peptides had no effects on migration. Our results indicate the central importance of several specific beta 1 integrins in human tumor cell migration and show the effectiveness of monoclonal antibody treatment in blocking this process in vitro.
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PMID:Monoclonal antibody and synthetic peptide inhibitors of human tumor cell migration. 236 27

The hemoregulatory peptide (pGlu-Glu-Asp-Cys-Lys, pEEDCK) is a potent inhibitor of stem cell recruitment, which is a major source of hematological complications after cytostatic tumor therapy. By preventing recruitment, pEEDCK can keep hemopoietic stem cells in their normal nonproliferative state and in this way prevent damage by certain cell cycle-specific cytostatic drugs. pEEDCK could play a role as hemoprotector in tumor chemotherapy. As a thiol-containing peptide, pEEDCK is highly sensitive to oxidation, resulting in the formation of a dimer. Although monomeric pEEDCK is a strong inhibitor of colony-forming units-granulocyte/macrophage (CFU-GM) clonal growth, the dimer was previously found to enhance colony-stimulating factor-triggered CFU-GM colony formation. It seemed, thus, necessary to find methods that avoid undesired dimerization reactions. A solid phase strategy for pEEDCK synthesis is presented. The primary synthetic product, S-tert-butyl-sulfenyl-pEEDCK, was purified and stored with the thiol-protecting group remaining attached. Conversion to active monomeric pEEDCK was achieved by reductive treatment in situ before application and removal of tert-butyl-mercaptane in vacuo. The activation reagent (dithioerythritol) prevented reoxidation also in culture media, where unprotected peptide was oxidized rapidly (t1/2 less than 13 min). The purified synthetic peptide was found to be a potent inhibitor of CFU-GM colony formation (IC50 = 1.1 x 10(-12) M) in vitro. It was also found to inhibit colony formation of some leukemic cell lines (HL-60, RAJI) although at much higher concentrations (10(-8) to 10(-9) M). Friend leukemia cells were not inhibited in the dose range where CFU-GM were sensitive.
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PMID:Hemoregulatory peptide pGlu-Glu-Asp-Cys-Lys: a new synthetic derivative for avoiding dimerization and loss of inhibitory activity. 240 29

Trophoblast-specific beta 1-glycoprotein (TSG, SP-1) has been isolated from retroplacental blood serum by the usual techniques. Together with the purified TSG, an antigen (TSGfs) possessing partial immunochemical identity with TSG, has been isolated. This antigen, with molecular mass 25 KD, contains virtually no fucose nor neuraminic acid and differs from TSG in a lower content of arginine, tyrosine and aspartic acid. In addition, a low-molecular weight fragment of the TSG molecule (TSGhs), partially identical immunochemically with TSG and fully identical immunochemically with TSGfs, has been obtained by partial acid hydrolysis of TSG. The partial acid hydrolysis of TSG yields TSGhs and high-molecular weight fragments with molecular masses greater than 160 KD which also exhibit a partial identity with TSG. The results provide evidence for the occurrence of a labile linkage bonding the two parts of the TSG molecule which carry different immunochemical determinants.
Tumour Biol 1986
PMID:An immunochemical study of trophoblast-specific beta 1-glycoprotein and its fragments. 242 27

We have previously shown that Rous sarcoma virus variants that carry the cellular homolog (c-src) of the viral src gene (v-src) do not transform chicken embryo fibroblasts. We also have shown that replacement of sequences upstream or downstream from the BglI site of the cellular src gene with the corresponding regions of v-src restored transforming activity to the hybrid genes. Since there are only six amino acid changes between p60c-src and p60v-src within the sequences upstream from BglI, we constructed chimeric molecules involving v-src and c-src to determine the effect of each amino acid substitution on the biological activities of the gene product. We found that the change from Thr to Ile at position 338 or the replacement of a fragment of c-src containing Gly-63, Arg-95, and Thr-96 with a corresponding fragment of v-src containing Asp-63, Trp-95, and Ile-96 converted p60c-src into a transforming protein by the criteria of focus formation, anchorage-independent growth, and tumor formation in newborn chickens. These mutations also resulted in elevation of the protein kinase activity of p60c-src.
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PMID:Amino acid substitutions sufficient to convert the nontransforming p60c-src protein to a transforming protein. 243 97

The interaction of cells with extracellular matrix components such as fibronectin, vitronectin, and type I collagen has been shown to be mediated through a family of cell-surface receptors that specifically recognize an arginine-glycine-aspartic acid (RGD) amino acid sequence within each protein. Synthetic peptides containing the RGD sequence can inhibit these receptor-ligand interactions. Here, we use novel RGD-containing synthetic peptides with different inhibition properties to investigate the role of the various RGD receptors in tumor cell invasion. The RGD-containing peptides used include peptides that inhibit the attachment of cells to fibronectin and vitronectin, a peptide that inhibits attachment to fibronectin but not to vitronectin, a cyclic peptide with the opposite specificity, and a peptide, GRGDTP, that inhibits attachment to type I collagen in addition to inhibiting attachment to fibronectin and vitronectin. The penetration of two human melanoma cell lines and a glioblastoma cell line through the human amniotic basement membrane and its underlying stroma was inhibited by all of the RGD-containing peptides except for the one that inhibits only the vitronectin attachment. Various control peptides lacking RGD showed essentially no inhibition. This inhibitory effect on cell invasion was dose-dependent and nontoxic. A hexapeptide, GRGDTP, that inhibits the attachment of cells to type I collagen in addition to inhibiting fibronectin- and vitronectin-mediated attachment was more inhibitory than those RGD peptides that inhibit only fibronectin and vitronectin attachment. Analysis of the location of these cells that were prevented from invading indicated that they attached to the amniotic basement membrane but did not proceed further into the tissue. These results suggest that interactions between RGD-containing extracellular matrix adhesion proteins and cells are necessary for cell invasion through tissues and that fibronectin and type I collagen are important for this process.
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PMID:Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides. 245 Jan 1

The ras family of proto-oncogenes can be activated into transforming genes by single point mutations resulting in p21 products with amino acid substitutions at positions 12, 13 and 61. Here we describe a monoclonal antibody designated R256 which reacts specifically with a synthetic peptide corresponding to amino acids 5 to 16 of ras p21 activated by the substitution of arginine for glycine at position 12. It does not react with peptides representing other activating substitutions at position 12. Western blot studies showed that R256 reacts specifically with recombinant ras p21 containing an arginine-12 substitution but is unreactive with the normal glycine-12 recombinant p21. R256 binds the activated Kirsten p21 in human lung tumor cell line A2182, which contains an activated arginine-12 p21. R256 is also specific for arginine-12 p21 extracted from NIH3T3 cells transformed by the viral Harvey-ras p21, containing arginine at 12, and is not reactive with transformants containing activated p21s with valine, serine, aspartic acid, glutamic acid, cysteine or normal glycine at position 12. When R256 was used to test for expression of arginine-12 p21 in tissues of transgenic mice containing an MMTV/v-Harvey-ras transgene, the monoclonal antibody was able to determine that the arginine-12 p21 transgene product was present in breast tumors but not in normal tissues. The ability of R256 to react specifically with arginine-12 p21 may prove to be valuable in the study of ras oncogenesis in model systems and in determining the presence of arginine-12 p21 in human tumors.
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PMID:Characterization of monoclonal antibody R256, specific for activated ras p21 with arginine at 12, and analysis of breast carcinoma of v-Harvey-ras transgenic mouse. 247 86

Site-specific covalent modification of monoclonal antibodies at the oligosaccharide offers advantages over more conventional modification processes that involve direct attachment at tyrosine, lysine or glutamic/aspartic acid side chains. Using the site-specific modification process, attachment sites on the antibody are distal to the antigen-binding region. Thus, homogeneity of antigen-binding properties and affinity for the unmodified protein are preserved. Furthermore, higher derivatization ratios with no resultant loss of immunoreactivity can be achieved for monoclonal antibodies modified at the oligosaccharide. In vivo biodistribution and tumor localization studies in nude mouse models suggest that antibodies radiolabeled at their oligosaccharide might represent improved immunoscintigraphic reagents. In a variety of tumor xenograft models, site-specific modified 111In-labeled antibody conjugates localized to the tumor site with little non-specific localization in other tissues or organs. The degree of localization at the target site was substantially greater than that of 111In-labeled antibodies directly modified at the tyrosine side chain. Preliminary studies with 212Bi- and 90Y-labeled antibodies modified at the oligosaccharide indicate that both of these radioisotopes have immunotherapeutic potential. Because of its preferential uptake by the kidney, the use of 212Bi may be best suited for tumors localized within the peritoneal cavity, such as ovarian and colorectal carcinomas. The toxicity of 90Y at high specific activities suggests that a regimen of repeated smaller doses of this radioisotope is best suited for therapeutic use. Studies in tumor-bearing mouse models are currently underway to better define the optimal dosage and administration regimens for both of these radioisotopes when attached to site-specific modified antibodies.
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PMID:Radioimmunoscintigraphy and radioimmunotherapy in nude mouse models. Studies with site-specifically modified monoclonal antibodies. 251 52

We have analyzed the effect of the synthetic oligopeptides Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) and Gly-Arg-Gly-Glu-Ser-Pro (GRGESP), analogues to the fibronectin cell-binding sequence, on the formation of experimental lung metastasis. SR-BALB were injected alone or in conjunction with GRGDSP or GRGESP in the tail vein of BALB/c mice. Co-injection with GRGESP reduced by approximately 70% the number of metastatic colonies per mouse. However, co-injection with the closely related peptide GRGDSP, containing the conservative substitution Glu/Asp, did not affect metastatic behavior. GRGESP peptide anti-metastatic activity was not due to a toxic effect on tumor cells or on mice. In vitro adhesion assays testing for a possible effect of the peptide on cell-matrix interactions indicated that the GRGESP peptide did not affect cell adhesion to the matrix proteins tested.
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PMID:Inhibition of experimental metastasis of murine fibrosarcoma cells by oligopeptide analogues to the fibronectin cell-binding site. 252 34

Understanding the mechanisms involved in maintaining the integrity of the vascular endothelium is fundamental to studies on atherosclerosis, thrombosis, inflammation and tumor invasion. One of the essential aspects is the relationship between the endothelial cell (EC) layer and the underlying components of the basement membrane (BM). The importance of the biological role of the individual components of the BM in the promotion of EC adhesion is investigated. In this study suspensions of bovine corneal ECs (BCECs; 5 x 10(4)/ml) were used to investigate the adhesion of EC to collagen type IV and a mixture of fragments of the tetrameric molecule (IV-F, consisting of 75, 120 and 140 kD fragments), as well as collagen types I and III, coated at a 10-micrograms/ml concentration onto glass coverslips in vitro. Adhesion was quantified after 2 h of interaction by direct counting in the light microscope following fixation of the adherent cells. Collagens type IV and IV-F markedly promoted BCEC adhesion both in the presence or absence of 10 or 50% fetal calf serum, indicating that the integrity of the tetrameric molecule is not required for EC adhesion to collagen type IV, but can be replaced by high molecular weight fragments. Collagens type I and III increased EC adhesion in the absence of serum, although not in the presence of serum. Indirect evidence for a possible role of fibronectin in EC adhesion to type-IV collagen is given by the ability of the tetrapeptide (Arg-Gly-Asp-Ser (10 micrograms) to temporarily block (15-30 min) the adhesion-promoting effect of type-IV collagen. The nature of the adhesion sequences on the fragments of type-IV collagen remains to be elucidated.
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PMID:Interaction between endothelial cells and basement membrane components. In vitro studies on endothelial cell adhesion to collagen types I, III, IV and high molecular weight fragments of IV. 253 76


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