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

Analogues of somatostatin (SS) and luteinizing hormone-releasing hormone (LH-RH) activate tyrosine phosphatases in MIA PaCa-2 human pancreatic cancer cell line membranes and inhibit growth. We compared the substrates phosphorylated by epidermal growth factor (EGF) to those dephosphorylated by the SS analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and [D-Trp6]LH-RH in cancer cell lines such as MIA PaCa-2 (human pancreatic cancer), HCPC (hamster cheek pouch carcinoma), A-549 (human lung cancer), HT-29 (human colon cancer), and R3230AC (breast cancer). EGF phosphorylated proteins of 170, 65, and 60 kDa and analogues of SS and LH-RH promoted the dephosphorylation of these proteins in MIA PaCa-2 and HCPC cell lines. The EGF receptor is 170 kDa. pp60src (60 kDa) is known to be a substrate for EGF receptor. The LH-RH receptor is also 60 kDa. The effects of RC-160 and [D-Trp6]LH-RH were quantitatively different. Examinations of HT-29, A-549, and R3230AC cancer cell lines revealed no phosphorylation by EGF or dephosphorylation by RC-160 and [D-Trp6]LH-RH. In addition to the 170-, 65-, and 60-kDa proteins, 35-kDa proteins were also phosphorylated in some cancer cell lines. This work demonstrates that analogues of SS and LH-RH can reverse the effects of EGF biochemically as well as functionally.
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PMID:Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation and dephosphorylation of tyrosine residues of specific protein substrates in various tumors. 167 42

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

Laminin, a major basement membrane-specific glycoprotein, promotes the attachment, migration, and invasion of a variety of tumor cells. Since laminin is present in the perisinusoidal matrix of the liver, we studied its effects on liver colonization by human colon cancer cells (HM7, LiM6) previously shown to have liver-metastasizing ability in athymic mice. These malignant cells expressed high levels of a 32-kDa laminin-binding protein on Western blot analysis when compared to the low metastatic parental cell line. Coinjection of laminin alpha chain-derived peptides which contain the amino acid sequence Ile-Lys-Val-Ala-Val (IKVAV) significantly stimulated liver colonization as determined by liver weight (P < 0.005) and number of tumor nodules (P < 0.02) 3 weeks after splenic-portal inoculation into nude mice. No stimulation was seen with a control peptide containing the same amino acids but in a scrambled sequence. In contrast, the Tyr-Ile-Gly-Ser-Arg peptide from the laminin beta 1 chain significantly inhibited HM7 liver colonization. These differences were not due to alterations in the number of cells initially reaching the liver as determined by injection of [125I]iododeoxyuridine-labeled tumor cells, but retention in the liver was stimulated by the IKVAV-containing peptides. Flow analysis indicated that the IKVAV peptide may act, in part, by stimulating homotypic adhesion of tumor cells. These data suggest that interactions of colon cancer cells with the IKVAV site on laminin may play a role in the formation of metastatic foci in the liver through cell-cell or cell-substratum interactions which promote metastasis.
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PMID:The laminin alpha 1 chain Ile-Lys-Val-Ala-Val (IKVAV)-containing peptide promotes liver colonization by human colon cancer cells. 775 2

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


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