Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orotic acid, first discovered in ruminant milk, is an intermediate in the pyrimidine biosynthesis pathway of animal cells. Its synthesis is initiated by the formation of carbamoyl phosphate (CP) in the cytoplasm, with ammonia derived from glutamine. Ureotelic species also form CP in the first step of urea synthesis in liver mitochondria. For that, ammonia is derived from tissue fluid. When there is insufficient capacity for detoxifying the load of ammonia presented for urea synthesis, CP leaves the mitochondria and enters the pyrimidine pathway, where orotic acid biosynthesis is stimulated, orotic acid excretion in urine then increases. Orotic acid synthesis is abnormally high with hereditary deficiencies of urea-cycle enzymes or uridine monophosphate synthase. It is also elevated by ammonia intoxication and during feeding of diets high in protein, high in lysine with respect to arginine, or deficient in arginine, ornithine, and citrulline. Rats fed 1% orotic acid or diets deficient in urea-cycle amino acids develop fatty livers, which has not been demonstrated in other species. Humans consuming 6 g of orotic acid daily have not shown adverse effects. Rats fed 1% orotic acid or arginine-deficient diets also showed more and larger foci positive for gamma-glutamyl transpeptidase and more liver tumors after administration of carcinogens and partial hepatectomy. Orotic acid feeding was also associated with the tendency for development of larger mammary tumors induced by chemical carcinogens in rats and with development of urinary bladder calculi containing high concentrations of orotic acid in mice. Conditions that raise tissue orotic acid change purine-pyrimidine ratios. It is unknown whether tissue orotate concentrations play a role in the recently observed enhanced proliferation of cells in the colon of rats fed high-protein, high-fat diets or in the promotion of chemically induced colon cancer by intrarectal administration of ammonium acetate.
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PMID:Nitrogen-stimulated orotic acid synthesis and nucleotide imbalance. 154 44

Human colonic mucosa obtained from colon cancer resections ('normal') and from colectomies owing to ulcerative colitis (inflamed) were cultured for up to 48 h in vitro. The 3H-leucine incorporation in normal tissue decreased to 52% (p less than 0.001) at 48 h compared with 24 h. The protein synthesis in normal but not in inflamed explants was significantly (p less than 0.01) improved at 48 h, reaching 72% of the 24-h value, on additions of insulin and the protease inhibitors aprotinin, soyabean trypsin inhibitor, and N alpha-tosyl-L-lysine chloromethyl ketone to the culture medium. Inflamed tissue had significant protein losses of 15% after 24 h and 29% after 48 h in culture, and the excretion of precipitable 3H-leucine-labelled proteins could be as high as 20%/24 h. A slight protein loss was observed in normal tissue after 48 h in culture, but the excretion of labelled proteins was very low (3%). The prostaglandin E2 (PGE2) production in both normal and inflamed tissue displayed an increasing non-linear pattern with time in culture, with higher values for inflamed tissue. The PGE2 release profiles and the differences in basic protein metabolism between normal and inflamed human colonic biopsy specimens in culture might reflect important characteristics of the inflammatory process.
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PMID:Viability, prostaglandin E2 production, and protein handling in normal and inflamed human colonic mucosa cultured for up to 48 h in vitro. 158 8

In this study, a site-specific glycyl-tyrosyl-(N-epsilon-diethylenetriaminepentaacetic acid)-lysine (GYK-DTPA) immunoconjugate of the anti-carcinoembryonic antigen monoclonal antibody C46 (C46-GYK-DTPA) was characterized by immunohistological and immunofluorescence methods for reactivity with normal and neoplastic human tissues. In addition, pharmacokinetic studies assessed the ability of C46-GYK-DTPA labeled with 111In to localize to and image human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar patterns of reactivity with normal human tissues. C46 did not bind to the surface of normal human granulocytes, which indicates lack of reactivity with normal cross-reacting antigen. C46-GYK-DTPA reacted with 100% of the colon, breast and renal carcinomas examined and with two of three lung carcinomas, but did not react with any sarcomas, melanomas or lymphomas examined. Intravenously administered C46-GYK-DTPA-111In rapidly localized to and imaged LS174T human colon adenocarcinoma xenografts in nude mice, reaching maximal levels of about 25% of injected dose/g tumor within 1 day. No unusual localization to any non-tumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that in the blood. The accessible binding sites in 1 g tumors appeared to be saturated at an antibody dose between 100 micrograms and 1000 micrograms/mouse. Further, in a direct in vivo comparison, the site-specific conjugate C46-GYK-DTPA had more favorable pharmacokinetics and better tumor localization than a randomly derivatized C46 immunoconjugate (C46-DTPA). These findings suggest that the site-specific immunoconjugate C46-GYK-DTPA may be useful in the diagnosis and therapy of colon cancer and other adenocarcinomas expressing carcinoembryonic antigen.
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PMID:Carbohydrate-derivatized immunoconjugate of the anti-(carcinoembryonic antigen) monoclonal antibody C46: immunohistological reactivity and pharmacokinetic comparison with a randomly derivatized C46 immunoconjugate. 226 96

A human cell line BE, derived from an undifferentiated carcinoma of the colon, was studied for its response to the cytocidal effects of human immune interferon (IFN-gamma) alone and in combination with various double-standard RNAs (dsRNAs). BE cells were moderately refractory to 3-day treatment with IFN-gamma (10 to 300 units/ml) where only 5 to 30% reduction in colony formation occurred. A similar exposure interval to polyriboinosinic.polyribocytidylic acid [poly(I).poly(C)] (100 micrograms/ml) had no detectable effect on colony formation. In contrast, the lethal effect of the combination of IFN-gamma and poly(I).poly(C) was synergistic and this regimen produced a 40 to 80% reduction in colony formation. The cytocidal effects of the combination of IFN-gamma with varying concentrations of the dsRNAs poly(I).poly(C), polyriboadenylic.polyribouridylic acid [poly(A).poly(U)], polyriboinosinic.polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(ICLC)], and mismatched dsRNA [rIn.r(C13,U)n] were also examined. The concentration of the dsRNAs producing a 50% decrease in cell viability in combination with IFN-gamma (100 units/ml) was 6 micrograms/ml for poly(I).poly(C), 1 microgram/ml for poly(A).poly(U), 3 ng/ml for poly(ICLC), and 16 micrograms/ml for rIn.r(C13,U)n. DNA, RNA, and protein synthesis in IFN-gamma and poly(I).poly(C)-treated cells were reduced in a dose-dependent manner. However, there were no changes in either (2',5')oligoadenylate concentrations or in ribosomal RNA transcription following treatment with IFN-gamma and poly(I).poly(C). Thus, the synergism resulting from the combination of IFN-gamma and dsRNA appears to be mediated via another, as yet unknown, mechanism.
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PMID:Potentiation of the cytocidal effect of human immune interferon by different synthetic double-stranded RNAs in the refractory human colon carcinoma cell line BE. 308 Dec 54

The bifunctional chelating agents (BFCs), 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-1,4 ,8, 11-tetraacetic acid (BAT), 6-[p-(isothiocyanato)benzyl]-1,4,8, 11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (SCN-TETA), 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid (CPTA), and 1-[(1,4, 7,10,13-pentaazacyclopentadec-1-yl)methyl]benzoic acid (PCBA), were synthesized and conjugated to the anti-colorectal monoclonal antibody (mAB), 1A3, and antibody fragments, 1A3-F(ab')2, for radiolabeling with 64,67CU and comparison in animal models. In vivo metabolism studies were carried out in liver and kidneys in order to correlate the nature of the metabolites formed to the uptake and retention of the radiolabel in each organ. Animal biodistribution studies were performed in Golden Syrian hamsters bearing the GW39 human colon cancer tumors and in normal Sprague-Dawley rats. All conjugates showed good tumor uptake in hamsters. Biodistribution in rats showed that 64CU-BAT-2IT-1A3 had the lowest liver and kidney uptake of the intact 1A3 conjugates (p < 0.03), whereas in hamsters, there were no significant differences in liver and kidney uptake between the four intact BFC-1A3 conjugates. Tumor-bearing hamsters injected with 64CU-CPTA-1A3-F(ab')2 and 64CU-PCBA-1A3-F(ab')2 had from 3 to 7 times greater uptake in the kidneys than hamsters given 64CU-labeled BAT and SCN-TETA 1A3-F(ab')2 conjugates, while rats injected with 64Cu-CPTA-1A3-F(ab')2 and 64Cu-PCBA-1A3-F(ab')2 had nearly twice the uptake. The in vivo metabolism of the mAbs 1A3 and 1A3-F(ab')2 radiolabeled with 67Cu through the SCN-TETA, CPTA, and PCBA BFCs was investigated by excising the livers and kidneys of normal rats from 1-5 days post-injection of the radiolabeled conjugates. Liver and kidney homogenates were analyzed by size exclusion chromatography and thin layer chromatography (TLC). The size exclusion chromatography data showed that all of the 67Cu-labeled 1A3-F(ab')2 conjugates were > 85% degraded in the kidneys to small molecular weight metabolites by 1 day post-injection. In contrast, in the liver at 1 day post-injection, greater than 70% of the 67Cu-labeled 1A3 conjugates were unmetabolized. By day 5, a 35 kDa peak appeared in the liver of rats injected with the 67 Cu-labeled 1A3 conjugates, possibly due to transchelation of the 67Cu to proteins. Superoxide dismutase chromatographically elutes at the same retention time as this 67Cu-labeled metabolite. The TLC data indicate that the low molecular weight metabolite (< 5 kDa) of both 67Cu-CPTA-1A3 and 67Cu-CPTA-1A3-F(ab')2 conjugates co-chromatographed with a 67Cu-CPTA-epsilon-lysine standard. Our data suggest that chelate charge and lipophilicity play a large role in kidney retention of 64/67Cu-labeled BFC-1A3-F(ab')2 conjugates, while transchelation of the copper label appears to be the major factor for liver accumulation of 64/67Cu-labeled BFC-1A3 conjugates.
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PMID:Comparison of four bifunctional chelates for radiolabeling monoclonal antibodies with copper radioisotopes: biodistribution and metabolism. 885 65

A marked effect of charge modification on the uptake and phototoxicity of a photoimmunoconjugate (PIC) was demonstrated. A site-specific conjugation strategy was developed to attach the photosensitizer chlorin(e6) (c(e6)) to the F(ab')2 fragment of the murine antiovarian cancer monoclonal antibody OC125. Poly-L-lysine linkers carrying c(e6) with a cationic charge or by polysuccinylation with an anionic charge were used and covalently attached to partially reduced antibody via a heterobifunctional reagent. PICs were purified by column chromatography and were also radiolabeled with 125I. PIC binding and uptake were studied with a human ovarian cancer cell line, NIH-OVCAR-5, and a nonantigen-expressing colon cancer cell line, SW1116, and the data were compared with the binding and uptake of nonspecific rabbit IgG PICs. PICs with both cationic and anionic charges preserved antigen binding as shown by competition studies with native antibody, but the cationic PIC had up to 17 times higher cellular uptake of c(e6), probably due to enhanced internalization. The ratio of c(e6) to 125I retained by the cells varied with the likelihood of internalization and lysosomal degradation. The phototoxicity of the PICs generally varied with their uptake, but a correlation was found between lysosomal hydrolysis as measured by an increased cellular ratio of c(e6):125I and increased relative phototoxicity. These data suggest cationic PICs may have advantages for photoimmunotherapy of disseminated intracavity cancer following local administration.
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PMID:Effect of charge on the interaction of site-specific photoimmunoconjugates with human ovarian cancer cells. 891 58

Pretargeting with bispecific antibodies has been used successfully for tumor detection and is now considered for radioimmunotherapy. The advantages of bivalent haptens have been demonstrated in this context. A series of bivalent molecules allowing efficient labeling with radioactive iodine has been designed for use with this new technology. They were based on the histamine-hemisuccinate hapten and prepared by solid phase peptide synthesis. Simultaneous binding of two antibody molecules to one bivalent hapten was possible with low steric hindrance when the two hapten groups were attached to the lateral chains of lysine residues separated by a single amino acid. Bispecific antibodies to the hapten and to carcinoembryonic antigen were shown to mediate specific binding of the haptens to tumor cells in vitro. These experiments demonstrated that the bivalent hapten AG3.0, with a lysyl-D-tyrosyl-lysine connecting chain, possessed the best binding properties. This peptide was used to target iodine-125 to human colon cancer xenografts in nude mice. High tumor uptake and tumor to normal tissue ratios were observed. This peptide thus appears as a good candidate for further development. Asymmetric bivalent haptens, with one histamine-hemisuccinate and one diethylenetriaminepentaacetic acid group, have also been prepared and shown to be capable of binding simultaneously two specific antibody molecules. These peptides should be useful to target radioiodine to cells characterized by the expression of two different antigenic markers.
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PMID:Bivalent hapten-bearing peptides designed for iodine-131 pretargeted radioimmunotherapy. 925 51

Mutations in genes that lie in the retinoblastoma pathway have been implicated in the pathogenesis of many tumor types. Two critical components that determine progression from G1 to S include p16/CDKN2A and CDK4. Alterations in p16/CDKN2A have been well documented in multiple cancers, including melanoma. However, changes in CDK4 are apparently more rare. Only two alterations, both at codon 24, have been identified in CDK4: an activating arginine-to-cysteine transition and a germ-line arginine-to-histidine substitution in one French kindred. In a survey of 20 neuroblastomas, 17 uncultured metastatic melanomas, 33 uncultured primary uveal melanomas, 8 colon cancer cell lines, and 20 primary colon cancer samples, we found no evidence of mutations in exon 2 of CDK4. From our cell lines derived from metastatic melanomas, we detected two alterations in the functionally critical exon 2 of CDK4: a lysine-to-glutamine transition at codon 22 and the arginine-to-histidine mutation at codon 24. These findings document several novel changes in the p16-binding region of CDK4.
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PMID:Novel mutations in the p16/CDKN2A binding region of the cyclin-dependent kinase-4 gene. 942 66

Whereas bivalent fragments have been widely used for radio-immunotherapy, no systematic study has been published on the therapeutic performance of monovalent conjugates in vivo. The aim of our study was, therefore, to determine the therapeutic performance of (131)I-labeled Fab as compared to bivalent conjugates and to analyze factors that influence dose-limiting organ toxicity and anti-tumor efficacy. The maximum tolerated doses (MTDs) and dose-limiting organ toxicities of the (131)I-labeled anti-CEA antibody MN-14 [IgG, F(ab')2 and Fab] were determined in nude mice bearing s.c. human colon cancer xenografts. Mice were treated with or without bone marrow transplantation (BMT) or inhibition of the renal accretion of antibody fragments by D-lysine or combinations thereof. Toxicity and tumor growth were monitored. Radiation dosimetry was calculated from biodistribution data. With all 3 (131)I-labeled immunoconjugates [IgG, F(ab')2 and Fab], the red marrow was the only dose-limiting organ; MTDs were 260 microCi for IgG, 1,200 microCi for F(ab')2 and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG and 3 times higher as compared to F(ab')2. The MTD of all 3 immunoconjugates was increased by BMT by approximately 30%. In accordance with renal doses below 10 Gy, no signs of nephrotoxicity were observed. Despite lower absorbed tumor doses, at equitoxic dosing, Fab fragments were more effective at controlling tumor growth than the respective bivalent fragment or IgG, probably due to higher intratumoral dose rates. Our data indicate that the improved anti-tumor effectiveness of antibody fragments as compared to IgG and the higher myelotoxicity at comparably lower red marrow doses are most likely due to the higher initial dose rates observed with antibody fragments.
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PMID:Experimental studies on the role of antibody fragments in cancer radio-immunotherapy: Influence of radiation dose and dose rate on toxicity and anti-tumor efficacy. 968 14

Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine and the resulting conjugates could interact with DNA in a noncovalent bond to form a complex. Using pSV2-beta-galactosidase as a reporter gene, it has been demonstrated that exogenous gene was transferred into bovine aortic arch-derived endothelial cells (ABAE) and human malignant melanoma cell lines (A375) in vitro. In vivo experiments, exogenous gene was transferred into tumor vascular endothelial cells and tumor cells of subcutaneously transplanted human colon cancer LOVO, human malignant melanoma A375 and human hepatoma graft in nude mice. This system could also target gene to intrahepatically transplanted human hepatoma injected via portal vein in nude mice. These results are correlated with the relevant receptors (flt-1, flk-1/KDR) expression on the targeted cells and tissues.
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PMID:A novel gene delivery system targeting cells expressing VEGF receptors. 1032 85


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