Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of diazoketone analogs of amino acids and associated problems were investigated with N-phthaloyl-DL-alanine serving as a model. The carboxyl was activated by conversion to the acid chloride or, under mild conditions, to the mixed anhydride obtained with ethyl chloroformate or dicyclohexylcarbodiimide; the product was reacted with diazomethane. Deblocking the phthaloyl group with hydrazine gave 3-amino-1-diazo-2-butanone as a well-characterized solid salt and as a less stable oil. Further reactions of the blocked diazoketone of DL-alanine, such as conversion to alpha-haloketones, Wolff rearrangement, and deuterium exchange on C-1 were investigated. 3-A-mino-1-diazo-2-butanone had moderate inhibitory activity against mouse mammary adenocarcinoma in cell culture.
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PMID:Alanine derivatives with reactive groups. 64

One- and two-dimensional 1H NMR spectra were obtained for normal murine thymus and malignant lymphoma tissue, as well as for the supernatant fractions from high speed centrifugal separations. Crosspeaks in the two-dimensional spectra resembled those reported by others for adenocarcinoma and leukemic lymphoblast cells, assigned tentatively to the carbohydrate fucose. However, for the present systems, spectral analysis and the spectral response to addition of known compounds led to assignment of the crosspeaks as follows: 1.33-4.12 ppm, lactate anion; 1.33-4.26 ppm, threonine; 1.48-3.78 ppm, alanine. Differences between the NMR data for the normal and malignant specimens were only in the relative intensities of the peaks. No peaks characteristic of fucose were found in spectra of cytosol, tissue or membrane lipids. Thus, the NMR data for malignant lymphoma cells are significantly different from those for adenocarcinoma and leukemic lymphoblasts. The NMR characteristics of different types of cancer cell must be individually determined.
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PMID:Identification of lactate, threonine and alanine in rat thymus and tumorigenic lymphoid cells using 1H 2-D COSY NMR spectroscopy. 132 Mar 92

The goal of the present study was to assess the relative importance of receptor-bound and secreted plasminogen activator urokinase (u-PA) in generating cell-surface plasmin and fostering destruction of normal tissue by tumor cells. We first showed that active site-inhibited u-PA could displace endogenous u-PA from the surface of the human colon adenocarcinoma cell line HCT 116. We then prepared expression vectors for u-PA and for a mutant molecule in which the codon for the active site serine residue was changed to encode alanine. Expression of non-functional mutant u-PA decreased the level of cell-bound active u-PA by more than 95% via a mechanism that involved competition for receptor sites. Decreased cell-surface u-PA activity was associated with a decrease in cell-bound plasmin activity to undetectable levels, suggesting that receptor-bound u-PA plays an important role in the generation of plasmin on the cell surface. Transfectants that secreted eightfold to 20-fold elevated levels of active wild-type u-PA showed approximately 50% increases in cell-associated u-PA and only twofold to fourfold increases in cell-associated plasmin, suggesting that the role of secreted u-PA in generating cell-surface plasmin activity was relatively minor. In parent cells and both types of transfectants there was a good correlation between the amount of plasmin bound to the tumor cell surface and the extent to which a basement membrane substrate was degraded. These studies show that receptor-bound u-PA provides an efficient mechanism for plasmin generation on the surface of tumor cells, which, in turn, contributes significantly to their degradative potential.
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PMID:Effects of urokinase receptor occupancy on plasmin generation and proteolysis of basement membrane by human tumor cells. 164 83

Carboxypeptidase A (CP-A) and monoclonal antibody KS1/4 directed against an antigen on human lung adenocarcinoma cells (UCLA-P3) were derivatized by treatment with succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate and N-succinimidyl 3-(2-pyridyldithio)propionate, respectively. The derivatized proteins were reacted to produce thioether-linked enzyme-antibody conjugates. Sequential HPLC size-exclusion and DEAE chromatography separated the conjugate preparation from unreacted enzyme and antibody. On the basis of SDS-PAGE analysis and measurement of catalytic activity, the preparation contained approximately equal amounts of 1:1 and 2:1 (enzyme:antibody) conjugates; binding activity of the conjugate (1.8 x 10(5) molecules/cell) was similar to that of unreacted antibody. In vitro cytotoxicity studies with UCLA-P3 cells demonstrated the ability of cell-bound conjugate to convert the prodrug methotrexate-alpha-alanine (MTX-Ala) to methotrexate (MTX). In the absence of conjugate, ID50 values for MTX-Ala and MTX were 8.9 x 10(-6) and 5.2 x 10(-8) M, respectively. ID50 for the prodrug improved to 1.5 x 10(-6) M with cells containing bound conjugate. This potentiation of MTX-Ala cytotoxicity by conjugate-bound CP-A, which was at least 30-fold greater than that produced by a comparable amount of free enzyme, is attributed to enhanced effectiveness of MTX generated at the cell surface as opposed to the surrounding medium. Examination of the time course of cytotoxicity over a 96-h period showed that the conjugate-prodrug combination (at 2.5 x 10(-6) M) was nearly as effective as MTX in preventing cell replication. These results demonstrate the chemotherapeutic potential of carboxypeptidase-monoclonal antibody conjugates used in conjunction with MTX peptide prodrugs.
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PMID:Activation of methotrexate-alpha-alanine by carboxypeptidase A-monoclonal antibody conjugate. 173 45

The alpha 2 beta 1 integrin serves as either a specific cell surface receptor for collagen or as both a collagen and laminin receptor depending upon the cell type. Recently we established that the alpha 2 beta 1 integrin binds to a site within the alpha 1 (I)-CB3 fragment of type I collagen (Staatz, W. D., Walsh, J. J., Pexton, T., and Santoro, S. A. (1990) J. Biol. Chem. 265, 4778-4781). To define the alpha 2 beta 1 recognition sequence further we have prepared an overlapping set of synthetic peptides which completely spans the 148-amino acid alpha 1(I)-CB3 fragment and tested the peptides for ability to inhibit cell adhesion to collagen and laminin substrates. The minimal active recognition sequence defined by these experiments is a tetrapeptide of the sequence Asp-Gly-Glu-Ala (DGEA) corresponding to residues 435-438 of the type I collagen sequence. The DGEA-containing peptides effectively inhibited alpha 2 beta 1-mediated Mg2(+)-dependent adhesion of platelets, which use the alpha 2 beta 1 integrin as a collagen-specific receptor, to collagen but had no effect on alpha 5 beta 1-mediated platelet adhesion to fibronectin or alpha 6 beta 1-mediated platelet adhesion to laminin. In contrast, with T47D breast adenocarcinoma cells, which use alpha 2 beta 1 as a collagen/lamin receptor, adhesion to both collagen and laminin was inhibited by DGEA-containing peptides. Deletion of the alanine residue or substitution of alanine for either the glutamic or aspartic acid residues in DGEA-containing peptides resulted in marked loss of inhibitory activity. These results indicate that the amino acid sequence DGEA serves as a recognition site for the alpha 2 beta 1 integrin complex on platelets and other cells.
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PMID:Identification of a tetrapeptide recognition sequence for the alpha 2 beta 1 integrin in collagen. 201 71

As part of our studies into the role of tumour cell proteinases in cancer invasion, we have adapted a fluorogenic assay to measure the elastase activities of intact rat mammary adenocarcinoma cells using the elastase specific substrates Cbz-Ala-Ala-Pro-Val-6-aminoquinoline and Ac-Ala-Ala-Pro-Ala-7-amino-4-methylcoumarin. This is a sensitive assay which enables rapid (30-120 min) measurement of enzyme activities under conditions of physiological pH and ionic strength and can differentiate between cell-associated and secreted enzyme activities. As the substrates are non-toxic and the method is non-invasive, cells can be reclaimed for further studies. This method thus provides a useful means for screening intact cells for elastase activity. Cell-surface elastase extracts were inhibited by phenylmethylsulphonyl fluoride but not by EDTA, indicating that they are serine proteinases. Extracts also degraded insoluble elastin confirming that these rat mammary adenocarcinoma cells produce elastase.
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PMID:Cell associated elastase activities of rat mammary tumour cells. 209 Jan 6

Extensive biochemical studies have shown that mucin tumor antigens have a range of molecular sizes from 200 to greater than 1000 kDa. The molecular size of mucin antigens can be dramatically affected by the source and method of purification. Mucin antigens vary from 24 to 80% in carbohydrate content and their density is usually greater than 1.40 g/ml. Galactose and N-acetyl glucosamine are the predominant sugar residues in many mucins, whereas mannose is usually present in low levels or absent. The amino acids serine, threonine, alanine, glycine, and proline are abundant in mucins. An O-glycosidic linkage between the carbohydrate and protein of mucins is the most common linkage encountered. The gene encoding the core peptide for at least one mucin tumor marker, HMFG, has been identified, sequenced, and expressed. These findings may lead to a better understanding of the multiepitope nature of mucin tumor markers. The advent of hybridoma technology has yielded several monoclonal antibodies that have been used to identify the presence of tumor-associated mucins in the sera of cancer patients. Elevated levels of mucin antigens have been found in the serum of most patients with advanced adenocarcinomas. Many studies have shown that tumor-associated markers are useful in monitoring patients following cancer treatment. Clinically useful immunoassays have been developed for monitoring patients with ovarian, breast, and pancreatic adenocarcinomas. Although individual mucin tumor markers show limited utility in detecting early adenocarcinoma, recent studies using multiple mucin markers have suggested that early detection, at sensitivities greater than 50%, can be achieved.
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PMID:Mucin glycoproteins as tumor markers. 210 May 76

Altered gluconeogenesis is frequently observed in cancerous hosts. To define its derangements in the liver, we studied glucose and glycogen production in the perfused livers of tumor-bearing rats using 13C NMR spectroscopy. Nine Fischer 344 rats were inoculated with mammary adenocarcinoma. After 5 weeks, the livers were removed and perfused with Krebs buffer containing 8 mM L-[3-13C]alanine, and 13C NMR spectroscopy was performed. Nine pair-fed rats were studied as controls. The peak heights of glucose and glycogen in the 13C NMR spectra of the perfused livers and final perfusates of the two groups of rats were compared. We found comparable amounts of C1-labeled glucose and glycogen in the two groups, but C2- to C5-labeled and C6-labeled glucose and glycogen, as well as total 13C-labeled glucose and glycogen, appeared in smaller quantities in the tumor rats than in the pair-fed rats. These findings suggest that appreciable amounts of unlabeled glycerol were utilized by both groups, but less so by the tumor rats than the pair-fed rats. In addition, there was decreased production of oxaloacetate through pyruvate dehydrogenase and the Krebs cycle in the livers of the tumor rats, where the overall metabolism of alanine into glucose and glycogen was also reduced.
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PMID:Gluconeogenesis in the liver of tumor rats. 238 Dec 8

This work describes the molecular characterization of a human pancreatic cancer-associated antigen defined by a murine monoclonal antibody (DU-PAN-2). DU-PAN-2 antigen was isolated from a pancreatic adenocarcinoma cell line (HPAF) or patient's ascitic fluid, and the antigenic activity was monitored by competitive inhibition radioimmunoassay. Affinity chromatography and CsCl/guanidine HCl density gradient centrifugation were employed to remove other populations of mucin-type glycoproteins and noncovalently associated proteins, respectively. Three electrophoretically distinct components were detected by 1% agarose gel electrophoresis and were resolved by chromatography on Sepharose CL-4B. The major fraction (FII) was subjected to carbohydrate and amino acid analyses. The sum of threonine, serine, proline, glycine, and alanine comprised more than 50% of the amino acid residues. The saccharide units, O-glycosidically linked to the peptide via GalNAc, contained fucose, galactose, GlcNAc, GalNAc, and sialic acid. The total carbohydrate content of FI and FII was 80.8% and 77.4% by weight, respectively. The molecular weight of FII antigen showed two species of molecules of 1.45 X 10(6) and 4.59 X 10(6) by analytical sedimentation equilibrium. DU-PAN-2 antigen was susceptible to neuraminidase, pepsin, Pronase, and papain digestion. These results suggest that both protein components and sialic acid residues may play important roles in the binding of DU-PAN-2 antibody.
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PMID:Molecular characterization of a mucin-type antigen associated with human pancreatic cancer. The DU-PAN-2 antigen. 244 70

Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-alanine], an antibiotic isolated from Streptomyces chibanensis, inhibited the growth of NIH 3T3 cells transformed by the activated human c-Ha-ras gene but did not significantly inhibit the growth of normal NIH 3T3 cells. Surprisingly, upon treatment with azatyrosine most of the transformed cells apparently became normal. These apparently normal cells, named revertant cells, grew in the presence of azatyrosine and stopped growing when they reached confluency, and their normal phenotype persisted during prolonged culture in the absence of azatyrosine. The revertant cells did not grow in soft agar and scarcely proliferated in nude mice. The human c-Ha-ras gene present in transformed NIH 3T3 cells was still present in the revertant cells and was expressed to the same extent as in the original transformed cells, producing the same amount of activated p21. Treatment with azatyrosine caused similar conversion of NIH 3T3 cells transformed by activated c-Ki-ras, N-ras, or c-raf to apparently normal cells, but NIH 3T3 cells transformed by hst or ret were not exclusively converted by azatyrosine. Human pancreatic adenocarcinoma cells, which are known to contain an amplified activated c-Ki-ras gene and an amplified c-myc gene, were also converted to flat and giant revertant cells by treatment with azatyrosine.
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PMID:Permanent conversion of mouse and human cells transformed by activated ras or raf genes to apparently normal cells by treatment with the antibiotic azatyrosine. 267 4


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