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)

Transforming growth factor alpha (TGF alpha)-Pseudomonas exotoxin 40 (PE40) is a chimeric protein consisting of an N-terminal TGF alpha domain fused to a C-terminal 40-kDa segment of the Pseudomonas exotoxin A protein. TGF alpha-PE40 exhibits the receptor-binding activity of TGF alpha and the cell-killing activity of PE40. These properties make TGF alpha-PE40 an effective cytotoxic agent for cells that possess epidermal growth factor receptors (EGFR). However, the utility of this protein as an anticancer agent has been unclear because many normal tissues express EGFR and may be damaged by exposure to TGF alpha-PE40. To address this issue, we injected nude mice with a lethal inoculum of either A431 or HT29 human tumor cells that possess EGFR or with Chinese hamster ovary (CHO) tumor cells that lack EGFR. Animals were treated with a derivative of TGF alpha-PE40 in which the cysteine residues are replaced by alanine, termed "TGF alpha-PE40 delta cys," or with saline once a day for 5 days. Mice bearing EGFR+ tumor cells lived significantly (P less than 0.001) longer when treated with TGF alpha-PE40 delta cys compared with saline-treated controls (median survival: A431 cells, 51.5 vs. 25.5 days; HT29 cells, 101 vs. 47.5 days). TGF alpha-PE40 delta cys did not prolong the survival of mice bearing tumor cells that lack EGFR (median survival: CHO cells, 15.5 vs. 19.5 days). The only toxicity to normal tissues was mild periportal hepatic necrosis. These studies indicate that a therapeutic window exists in vivo for the use of some growth factor-toxin fusion proteins as anticancer agents.
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PMID:Transforming growth factor alpha-Pseudomonas exotoxin fusion protein prolongs survival of nude mice bearing tumor xenografts. 235 44

The purpose of this study was to evaluate whether heart glucose metabolism can account for elevated heart oxygen consumption in a tumor-bearing host. This is the first report of altered metabolism in perfused hearts from tumor-bearing animals. Glucose, glycerol, lactate, and amino acid metabolism was examined under steady-state conditions in isolated perfused hearts from sarcoma-bearing rats and compared to the metabolism in hearts from starved (96 hr) and fed control rats. Heart dry weight was reduced by 10% in tumor-bearing rats and by 30% in starved rats when compared to freely fed control animals. Cardiac glucose uptake was decreased in tumor-bearing rats (206 +/- 33 mumoles/hr/g dry wt) compared to both starved (298 +/- 18) and fed control rats (293 +/- 25). Hearts from both fed and starved controls released lactate and glycerol at significant rates during perfusion which was not evident in hearts from tumor-bearing rats. The release of individual amino acids from working hearts during perfusion was different among the animal groups with a severe depression of both glutamine and alanine release in tumor-bearing rats. In starved rats alanine release was normal although glutamine release was depressed by more than 50%. The net release of all amino acids was lowest in hearts from tumor-bearing rats, intermediate in the starved animals, and highest in the control animals, while the nonmetabolized amino acids (phenylalanine, tyrosine, methionine) were released at increased rates only from tumor-host hearts, indicating an increased net breakdown of some cardiac proteins in tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose uptake and amino acid metabolism in perfused hearts from tumor-bearing rats. 235 96

Antibody-drug conjugates containing a linkage susceptible to lysosomal hydrolases were constructed by coupling peptide-daunorubicin (DNR) derivatives to MAb. Using a modification in the method of Trouet et al, peptide derivatives of DNR containing the sequences Ala-Leu and Ala-Leu-Ala-Leu linked to drug via their carboxy terminus were prepared. Cleavage of these derivatives by lysosomal enzymes resulting in the release of free DNR was demonstrated. Human antitumor MAb were derivatized with either succinic anhydride or cis-aconitic anhydride to introduce spacer arms for coupling. Binding studies showed that MAb with a decrease of 12-20 amino groups retained greater than 70% of their immunoreactivity, a level deemed acceptable for constructing conjugates. Derivatized and native MAb were conjugated to peptide-DNR via a carbodiimide mediated reaction. None of the conjugates displayed cytotoxicity toward target tumor cell lines in vitro.
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PMID:Tumor reactive cis-aconitylated monoclonal antibodies coupled to daunorubicin through a peptide spacer are unable to kill tumor cells. 236 98

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

A monospecific polyclonal antiserum against deglycosylated human pancreatic tumor mucin was used to select human pancreatic mucin cDNA clones from a lambda gt11 cDNA expression library developed from a human pancreatic tumor cell line. The full-length 4.4-kilobase mucin cDNA sequence included a 72-base pair 5'-untranslated region and a 307-base pair 3'-untranslated region. The predicted amino acid sequence for this cDNA revealed a protein of 122,071 daltons containing 1,255 amino acid residues of which greater than 60% were serine, threonine, proline, alanine, and glycine. Approximately two-thirds of the protein sequence consisted of identical 20-amino acid tandem repeats which were flanked by degenerate tandem repeats and nontandem repeat sequences on both the amino-terminal and carboxyl-terminal ends. The amino acid sequence also contained five putative N-linked glycosylation sites, a putative signal sequence and transmembrane domain, and numerous serine and threonine residues (potential O-linked glycosylation sites) outside and within the tandem repeat position. The cDNA and deduced amino acid sequence of the pancreatic mucin sequence was over 99% homologous with a mucin cDNA sequence derived from breast tumor mucin, even though the native forms of these molecules are quite distinct in size and degree of glycosylation.
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PMID:Cloning and sequencing of a human pancreatic tumor mucin cDNA. 239 22

A 2-fold increase in hepatic alanine concentration was observed in rats bearing a Walker 256 carcinoma growing sub-cutaneously. Decreases were observed in the activities of both cytosolic and mitochondrial isozyme forms of L-alanine-2-oxoglutarate aminotransferase. Activities of two enzymes involved in a secondary pathway of haem synthesis involving alanine, L-alanine-4,5-dioxovalerate aminotransferase and the NADP-requiring isozyme form of 4-oxo-5-hydroxyvalerate dehydrogenase were also reduced but there was no change in liver porphyrin concentration. L-alanine-glyoxalate aminotransferase activity was unaffected. The results are discussed in relation to the utilisation of alanine as a gluconeogenic substrate in the tumor-bearing host.
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PMID:Increased liver alanine in the tumour-bearing host. Altered levels of some enzymes involved in alanine metabolism. 240 67

The substrate specificity determinants of protein kinase C are probed using synthetic peptides encompassing the major phosphorylation site serine 115 in bovine MBP. The results indicate that basic residues arginine 107 and 113 N-terminal to the phosphorylation site are essential for the substrate activity of the peptides. Substitutions of these basic residues by alanine cause a marked decrease in their substrate activity and the resulting peptide analogs become specific and rather potent inhibitors of protein kinase C. Leukemic cells are particularly abundant in protein kinase C and its substrate proteins, and the enzyme system has been shown to play a key role in cell growth. The agents that stimulate protein kinase C include tumor promoting phorbol esters (such as TPA) and mezerein, and the putative second messenger diacylglycerol. Many antineoplastic agents, on the other hand, inhibit the enzyme which include adriamycin, tamoxifen, alkyl-lysophospholipid, selenium, retinal and lipoidal amine CP-46, 665-1. Immunocytochemical studies of protein kinase C in leukemic cells indicate that it is localized in the plasma membrane, cytoplasm, nucleus and Golgi apparatus, and the subcellular distribution of the enzyme might be related to the phases of the cell cycle. TPA induces translocation of the enzyme to plasma membrane, suggesting an additional mode of action for the tumor promotor.
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PMID:Phospholipid/calcium-dependent protein kinase (protein kinase C) system: a major site of bioregulation. 243 6

In our previous report, monoclonal antibody PR92 has defined prostate- and breast tumor-associated PR92 antigen. The molecular nature of PR92 antigen, especially the epitope involved in specific interaction with PR92 monoclonal antibody, is described. PR92 antigen was purified from the cell extract or tissue culture medium of prostate cancer cell line DU145 by means of monoclonal antibody-coupled Sepharose 4B affinity chromatography, followed by a Sephacryl S-500 chromatography. Physical and chemical characterization, coupled with high-performance liquid chromatography, determined that PR92 antigen is a glycoprotein with a molecular weight of about 470,000, comprising repeating subunits of about 44,000. Sialic acid was found to form a critical part, while D-galactose and N-acetylgalactosamine were also involved, in the epitope structure. PR92 antigen is rich in serine, threonine, proline, glycine, and alanine and poor in aromatic amino acid residues. The carbohydrate moieties may be predominantly O-linked to polypeptide chains which contribute directly or indirectly to maintain the integrity of the epitope. Elucidation of the molecular nature of PR92 antigen may help understand the mechanism of shedding into the body fluids during tumor progression.
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PMID:Molecular characterization of the epitope in prostate and breast tumor-associated PR92 antigen. 246 8

The object of this study was to develop a sustained release implantable dosage form of a new silicone gel (PHYCON 6600R) which undergoes addition polymerization to produce a solid gel at ordinary temperature. Implantable PHYCON-drug composites were studied as a means of tumor therapy using 3',5'-diesters of 5-fluoro-2'-deoxyuridine (FUdR-Cn) as a model for antitumor drugs. Using an in vitro dissolution test, we found that the release characteristics of drugs from these preparations could be controlled by the addition of powdered L-alanine. In vivo studies of antitumor activity were carried out, using preparations containing the dodecyl ester (FUdR-C12) by measuring the lifespan of lymphoma-inoculated mice. Antitumor activity, reflected in increased lifespan, was shown to be greater following intraperitoneal administration of the PHYCON formulations (drug and L-alanine) than following injections of the drug alone. Our results suggest that sustained release implantable formulations of antitumor drugs in PHYCON might be suitable for tumor chemotherapy.
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PMID:Application of new silicone gel to sustained release dosage form of antitumor drug. 253 5

A series of oligopeptides have been synthesized that are structurally related to the natural agent netropsin. The binding constants to double-stranded polynucleotides as well as the cytostatic activity against both murine human tumor cell lines and the in vitro activity against a range of DNA and RNA viruses have been determined for these novel compounds and some of their synthetic precursors. 1-Methyl-5-nitropyrrole-2-carboxylic acid methyl ester (4), N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanine tert-butyl ester (28), and N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanyl-L-alanine tert-butyl ester (29) showed modest inhibitory effect on tumor cell proliferation (CD50 = 26-85 micrograms/mL). Of all the compounds that were evaluated, 28 proved the most potent antiviral agent. It was inhibitory to parainfluenza-3 virus and Coxsackie virus B4 in Vero cells at a concentration of 20 micrograms/mL.
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PMID:Synthesis, DNA binding, and biological evaluation of synthetic precursors and novel analogues of netropsin. 254 Mar 32


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