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)

Lipopeptides, carrying the N-terminal lipoamino acid 2-(palmitoylamino)-6,7-bis(palmitoyloxy) heptanoic acid (Pam3Adh-OH, 1), were obtained by solid-phase synthesis and by synthesis in solution. 2-Amino-6,7-dihydroxyheptanoic acid (Adh) can be regarded as a methylene analogue of S-glycerylcysteine, the N-terminal amino acid of lipoprotein from the outer cell membrane of Escherichia coli (a methylene group substitutes for the sulfur atom). The lipopeptides Pam3Adh-Ser-Ser-Asn-Ala 2a-d, in which the four possible stereoisomers of Pam3Adh-OH (2S,6S)-1 (1a), (2S,6R)-1 (1b), (2R,6S)-1 (1c), and (2R,6R)-1 (1d) are linked to the naturally occurring sequence Ser-Ser-Asn-Ala of the N-terminus of lipoprotein, and also Pam3Adh-Ser-(Lys)4 [2S,6S)-3), with a peptide part rendering the molecule water soluble, were capable of stimulating murine splenocytes polyclonally in vitro, as determined in a proliferation assay and in a hemolytic plaque assay against trinitrophenylated sheep erythrocytes. The diastereomers (2S,6S)-2 and (2R,6S)-2 with S-configurated C-6 were more active than the diastereomers (2S,6R)-2 and (2R,6R)-2 with R-configurated C-6; a change of the configuration at C-2 had less effect on the stimulatory activity. (2S,6S)-2 and (2S,6S)-3 are potent immunoadjuvants. A significantly enhanced primary immune response against trinitrophenylated sheep erythrocytes was obtained in vitro at lipopeptide concentrations of about 5 micrograms/mL and an immunization dose of 10(7) sheep erythrocytes/mL. Balb/c mice, which were immunized with a mixture of ovalbumin and (2S,6S)-2 or (2S,6S)-3, respectively, had a substantially higher antiovalbumin titer 28 days after immunization than mice which had received ovalbumin, (2S,6S)-2 or (2S,6S)-3 alone. Finally, the novel lipopeptides constitute potent macrophage activators: (2S,6S)-3 was able to induce tumor cytotoxicity against the tumor cell line L929 in bone marrow derived macrophages.
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PMID:Lipopeptides containing 2-(palmitoylamino)-6,7-bis(palmitoyloxy) heptanoic acid: synthesis, stereospecific stimulation of B-lymphocytes and macrophages, and adjuvanticity in vivo and in vitro. 206 69

The ribose moiety of 5-fluorouridine (FUR) was oxidized with periodate and the product was bound through a poly(L-lysine) bridge to monoclonal antibodies, denoted SF25MAb, reactive with a human colon carcinoma LS180. The antibody was linked via its polysaccharide (previously oxidized with periodate) to the poly(L-lysine)-drug conjugate. The linking of FUR-poly(L-lysine) to the antibody markedly increased the latter's binding to the tumor cells. A relatively lower increase was also observed with conjugates of nonrelated antibodies, such as anti-hepatitis B surface antigen and anti-epidermal growth factor receptor antibodies. The pharmacological activity of the specific conjugate FUR-poly(L-lysine) -SF25MAb was higher than that of the drug-substituted polymer alone. The poly(L-lysine) bridge caused toxic effects in vivo, even though substituted both by FUR and by antibody. Therefore, the additional unreacted lysyl residues were blocked by succinylation. Partial blocking of free amino groups on the conjugate rendered it nontoxic but decreased its cell-binding capacity, though to a level still higher than that of the original unmodified antibody. The pharmacological activity of the specific conjugate after blocking was also reduced and necessitated prolonged incubation periods or higher concentrations. Following periodate oxidation and reduction, FUR was as effective as the clinically preferred compound 5-fluoro-2'-deoxyuridine in vitro and in vivo, against the LS180 colon carcinoma. Experiments in nude mice, with LS180 tumor subcutaneous xenotransplants, showed that FUR-poly(L-lysine)-SF25MAb (blocked by succinylation) was not toxic and was effective in the retardation of tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A conjugate of 5-fluorouridine-poly(L-lysine) and an antibody reactive with human colon carcinoma. 209 21

An enzyme-linked immunosorbent assay (ELISA) has been developed to detect antibodies against surface components of rat islet and spleen lymphocytes. Live islet tumor RIN5 AH cells expressing characteristic ganglioside target antigens or rat spleen cells were immobilized onto wells of microtiter polystyrene plates precoated with poly-l-lysine and then incubated with test or normal rat sera. Cell surface-bound antibodies were quantitated after reaction with horseradish peroxidase-conjugated rabbit anti-rat Ig. With this assay, 46% (6/13) of sera from diabetes-prone BB rats and 100% (8/8) of sera from rats treated with complete Freund's adjuvant/streptozotocin (CFA/STZ) prior to immunization with RIN cells had islet cell surface antibodies: 54% (7/13) and 75% (6/8), respectively, were positive for lymphocyte antibodies (defined as the HRP anti-rat Ig binding exceeding the mean + 2SD of control group values). SDS polyacrylamide gel electrophoresis followed by immunoblotting analysis suggested that the islet cell antibodies in sera from the BB and CFA/STZ rats recognized RIN-cell components that were different in their molecular weights. These antigens were not detectable on spleen cells indicating that the ELISA described can be used to quantitate levels of islet cell specific antibodies which possibly reflect beta cell damage with progression to islet degeneration in the rat.
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PMID:Detection of antibodies to islet cell and splenic lymphocytes in diabetes-prone BB and adjuvant-streptozotocin treated Lewis rats by ELISA and immunoblot analysis. 209

To be capable of selective killing of tumor cells, the non-selective Pseudomonas aeruginosa exotoxin A must have its cell-binding domain inactivated or removed and then be chemically linked to, or genetically fused with, a specific targeting agent. In the present study, epsilon-NH2 groups of lysine residues of the cell-binding domain of exotoxin A were extensively propionylated with N-succinimidyl-3-propionate (NSP). The NSP-treated exotoxin retained its cytocidal ADP-ribosyltransferase activity, but it could no longer bind to, and inhibit the proliferation of, Friend murine erythroleukemia cells. Cytotoxicity (i.e., the ability to inhibit proliferation) for the Friend erythroid cells was restored completely to the NSP-inactivated exotoxin by conjugating it to ADIF, an autocrine factor secreted by chicken erythroleukemia cells which selectively inhibits the differentiation of erythroid cells such as Friend erythroleukemia cells without inhibiting their proliferation.
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PMID:The cytotoxicity of Pseudomonas exotoxin A, inactivated by modification of the cell-binding domain I, is restored when conjugated to an erythroid cell-specific targeting agent. 210 50

Monoclonal antibodies were raised against a synthetic NH2-terminal myristoyl tetrapeptide (N-myristoyl-Gly-Ser-Ser-Lys) which is characteristic of an NH2-terminal portion of pp60src, the transforming protein of src-oncogene. The antibody reacted with the albumin conjugated with both the N-myristoyl and N-lauroyl-tetrapeptides, but concentrations at which 50% of the immunoreaction was inhibited were 5 pmol for the N-myristoyl and 830 pmol for N-lauroyl tetrapeptidyl albumin. On the other hand, N-palmitoyl tetrapeptidyl and underivatized albumin, and Gly-Ser-Ser-Lys-Ser-Lys-Pro-Lys octapeptide had no effects. These results suggest a high affinity of the antibody for an N-myristoyl-Gly-Ser-Ser-Lys moiety. src-Oncogene products in Rous sarcoma virus-transformed cells and human colon carcinoma tumor cells were selectively identified as myristoylated pp60src by immunoprecipitation analyses with the antibody.
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PMID:Myristoylated src-oncogene products are potently detected by the monoclonal antibody to the NH2-terminal myristoyl-Gly-Ser-Ser-Lys src-peptide. 211 93

Supernatant obtained from granulocytes stimulated in the presence of cytochalasin B by the chemotactic peptide N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl- lysine displayed an inhibitory effect on the plasmin-dependent conversion of tumor urokinase-type plasminogen activator proenzyme (pro-uPA) to the active form of uPA. Moreover, the supernatant was also found to inhibit the fibrinolytic activity of human vulva (A431) and breast (MCF7) carcinoma cell lines, which contain large amounts of pro-uPA, by 87% and 96%, respectively. By using eglin C (elastase inhibitor) and a monoclonal antibody to elastase (proteolytic activity blocker of the enzyme), elastase was identified as the key enzyme of the supernatant in these phenomena. Purified elastase converted pro-uPA to an enzymatically inactive molecule composed of two polypeptide chains of Mr = 33,000 and 22,000 linked to each other by a disulfide bond. Elastase-containing granulocytes were identified by immunohistochemistry techniques in the tissues of squamous cell carcinoma and adenocarcinoma of uterus. The cells were found close to the tumor cells and in the stroma surrounding the tumor nests. By immunohistochemical staining, uPA was also found in the tumor cells. Evidently, elastase released by chemotactically activated granulocytes, which are attracted into tumor tissues, may inhibit the conversion of pro-uPA to enzymatically active uPA in the tumor cells.
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PMID:Inactivation of human tumor cell pro-urokinase by granulocyte elastase. 212 85

A consensus sequence in parvovirus nonstructural protein NS1 has been predicted to be an ATP-binding domain associated with an ATPase and a DNA helicase activity. To investigate the function of NS1 in viral gene expression, a site-directed mutagenesis converting NS1 lysine 405 to serine in parvovirus H-1 was carried out by the polymerase chain reaction. As shown previously, a parvovirus genome containing a deleted NS1 gene was excised from a bacterial plasmid and replicated when a wild-type NS1 gene was provided in trans but failed to be excised and replicate when the mutant NS1 gene was supplied. Interestingly, the serine 405 mutation totally lost the activity of trans activation on the virus late promoter (P38) in a chloramphenicol acetyltransferase (CAT) assay and it lost evidence for cytotoxicity in two tumor cell lines (HeLa Gey and NB324K). The serine 405 NS1 protein was translocated normally to the nucleus. These results suggest that the NS1 lysine 405 of H-1 in its putative purine nucleotide-binding site is essential for viral DNA replication and that this domain may be involved in the regulation of the P38 promoter by an unknown mechanism. The loss of NS1 cytotoxicity on tumor cells suggests that NS1 expression is the major cause of cell killing by parvoviruses, which may facilitate further study of the mechanism of oncosuppression by parvoviruses.
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PMID:Mutation of lysine 405 to serine in the parvovirus H-1 NS1 abolishes its functions for viral DNA replication, late promoter trans activation, and cytotoxicity. 214 94

In view of the critical role that the Ca2+- and phospholipid-dependent enzyme protein kinase C (PKC) plays in mediating proliferative responses to a number of growth factors, hormones, and tumor promoters, it is thought that selective PKC inhibitors may provide a new class of antiproliferative drugs. Established PKC inhibitors include three major classes of agents: agents that compete with the substrate ATP, agents that compete with the protein substrate, and agents that both compete with ATP and interact with the cofactor phosphatidylserine (PS). In this report, we have characterized the interactions between PKC and N-myristyl-Lys-Arg-Thr-Leu-Arg, a myristylated analogue of a synthetic peptide substrate of PKC. We determined that the myristylated peptide was a novel PKC inhibitor that interacted with PS as well as competed with the protein substrate of PKC. The inhibitory activity of the peptide was conferred by myristylation. We found that the myristylated peptide antagonized Ca2+- and PS-activated PKC with an IC50 of 75 microns, whereas the nonmyristylated peptide lacked this inhibitory activity. A fully active, Ca2+- and PS-independent catalytic fragment of PKC can be generated by limited proteolysis. Although the myristylated peptide was a very poor PKC substrate, this peptide inhibited the catalytic fragment of PKC by apparent competition with the phosphoacceptor substrate histone IIIS with an IC50 of 200 microM, whereas the nonmyristylated peptide showed no inhibitory activity against the catalytic fragment. Thus, the myristylated peptide may serve as a model for the development of selective PKC inhibitors, because its inhibitory mechanism exploits the substrate specificity of PKC, as well as the novel regulation of the enzyme. Furthermore, since endogenous PKC substrates include acylated proteins, the observations that we report here concerning a myristylated synthetic peptide suggest that acylation of proteins may be important in the regulation of PKC activity in vivo.
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PMID:N-myristyl-Lys-Arg-Thr-Leu-Arg: a novel protein kinase C inhibitor. 215 82

Tumor cells attach, degrade, and migrate through basement membranes as they metastasize. Laminin, a major glycoprotein of basement membranes, promotes the metastatic activity of tumor cells by stimulating the attachment and migration of the cells and their secretion of collagenase IV. We have identified a synthetic peptide of 19 amino acids (Cys-Ser-Arg-Ala-Arg-Lys-Gln-Ala-Ala-Ser-Ile-Lys-Val-Ala-Val-Ser-Ala-Asp -Arg) from the sequence of the A chain of laminin that increases experimental metastases of the lungs by murine melanoma cells. The peptide is active when injected either intravenously or intraperitoneally. The peptide increased collagenase IV activity, a key enzyme in the breakdown of basement membranes, to the same extent as laminin. This peptide represents an active site on laminin for promotion of the metastatic phenotype and generates a probe for studying the regulation of malignant activities.
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PMID:Identification of an amino acid sequence from the laminin A chain that stimulates metastasis and collagenase IV production. 215 66

The effects of cortisol, its steric analog 11-epicortisol, and lysine vasopressin (LVP) on DNA and RNA synthesis in isolated adrenocorticotropic hormone-secreting human pituitary tumor cells obtained by transsphenoidal surgery were studied using [3H]thymidine incorporation in DNA and [3H]uridine in RNA. Cortisol suppressed RNA and, to a greater extent, DNA synthesis in these cells. This could explain the slow growth of pituitary tumors in patients with Cushing's disease and the rapid growth of Nelson's pituitary tumors after bilateral adrenalectomy. 11-Epicortisol also suppressed RNA synthesis, but it had a stimulatory effect on DNA synthesis, which indicates a high specificity of glucocorticoid receptors. When applied together with cortisol, 11-epicortisol antagonized the suppressive effects of cortisol on DNA synthesis. Although LVP stimulated RNA synthesis, it suppressed DNA synthesis in most of the tumor cells.
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PMID:The effects of cortisol, 11-epicortisol, and lysine vasopressin on DNA and RNA synthesis in isolated human adrenocorticotropic hormone-secreting pituitary tumor cells. 215 95


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