Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic enzymes may facilitate tumor invasion by histolysis of the surrounding tissue and inhibit tumor growth in the course of host defense reactions. Using chromogenic peptide substrates, we looked for proteolytic activities related to carcinogenesis in serum and tumor extracts of rats with benzopyrene sarcomas. The enzymatic hydrolysis of two substrates (Boc-(Ala)2-p-nitroanilide and Bz-Lys-p-nitroanilide) was significantly decreased in the sera of tumor-bearing animals (P less than 0.01). This loss of proteolytic activity was highly correlated to tumor growth, so these enzymes might become useful as new tumor markers. In the tumor extracts, we found the Boc-(Ala)2-p-nitroanilide cleaving activity increased with tumor weight, whereas the Bz-Lys-p-nitroanilide cleaving activity did not exhibit any correlation to tumor growth. Studies on the potential use of these results for cancer patients are indicated.
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PMID:Proteolytic enzymes as new tumor markers in rats with benzopyrene sarcoma. 356 7

The effects of amino acids on the enhanced agglutinability of bladder cells with concanavalin A induced by subcarcinogenic treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine were examined. The amino acids examined were L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-glycine, DL- and L-histidine, L-hydroxyproline, L-isoleucine, D- and L-leucine, L-lysine, L-methionine, DL- and L-phenylalanine, L-proline, L-serine, L-threonine, DL-, D- and L-tryptophan, L-tyrosine and D- and L-valine. They were added to powdered diet at a concentration of 2.0%. L-Leucine, L-isoleucine, L-valine, DL- and D-tryptophan prolonged the period during which the bladder cells showed enhanced agglutinability with concanavalin A. Leupeptin, a protease inhibitor, and L-leucyl-L-leucine were also examined at a concentration of 0.1% because of their similar chemical structures, and were found to have the same effect. The tumor-promoting effects of DL-tryptophan and leupeptin have already been established by in vivo carcinogenesis experiments. The effects of L-leucine, L-isoleucine, L-valine, D-tryptophan and L-leucyl-L-leucine, detected by this short term assay, suggest that these compounds may also be promoters of bladder cancer in rats.
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PMID:Detection of amino acids as possible promoters of bladder cancer in rats by measuring their enhancement of agglutination of bladder cells by concanavalin A. 716 May 80

Inhibition studies were carried out to study possible cross-reactivity between a peptide fragment of the Epstein-Barr virus nuclear antigen, EBNA-1, and keratin/collagen. The 20-amino acid peptide (pAG), derived from a glycine-alanine repeat region of EBNA-1, uniquely makes up about one-third of the viral protein and is a dominant IgA antigenic epitope in patients with nasopharyngeal carcinoma (NPC). A small percentage of normal human sera (NHS) also binds pAG and this reactivity is examined in this study. Ten percent (2/20) and 13.4% (2/15) of IgA-pAG-positive NPC sera and NHS, respectively, were significantly inhibited by keratin in a competitive ELISA system. Conversely, 31.6% (6/19) and 30.8% (4/13) of IgA-keratin-positive NPC sera and NHS, respectively, were significantly inhibited by pAG. This indicated minimum cross-reactivity between IgA serum antibodies to EBNA-1 and keratin. Using collagen as inhibitor, none of 18 and only 2/13 IgA-pAG-positive NPC sera and NHS, respectively, were inhibited. In the collagen ELISA system, only 2/19 (10.5%) and 4/25 (16%) of IgA-collagen-positive NPC sera and NHS, respectively, were inhibited with pAG. Therefore, cross-reactivity with collagen was also low. IgA-pAG-positive NHS may therefore not be a false positive phenomenon, but whether it may represent an early serological profile related to NPC carcinogenesis remains to be determined.
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PMID:Serum IgA cross-reactivity between glycine-alanine repeat sequence of EBNA-1 and keratin or collagen in nasopharyngeal carcinoma. 751 12

Nickel(II) compounds are established human carcinogens, but the molecular mechanisms underlying their activity are only partially known. One mechanism may include mediation by nickel of promutagenic oxidative DNA damage that depends on Ni(II) binding to chromatin. To characterize such binding at the histone moiety of chromatin, we synthesized the peptide CH3CO-Cys-Ala-Ile-His-NH2 (L), a model of the evolutionarily conserved motif in histone H3 with expected affinity for transition metals, and evaluated its reactivity toward Ni(II). Combined spectroscopic (UV/vis, CD, NMR) and potentiometric measurements showed that, at physiological pH, mixtures of Ni(II) and L yielded unusual macrochelate complexes, NiL and NiL2, in which the metal cation was bound through Cys and His side chains in a square-planar arrangement. Above pH 9, a NiH-3L complex was formed, structurally analogous to typical square-planar nickel complexes. These complexes are expected to catalyze oxidation reactions, and therefore, coordination of Ni(II) by the L motif in core histone H3 may be a key event in oxidative DNA base damage observed in the process of Ni(II)-induced carcinogenesis.
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PMID:Interactions of nickel(II) with histones. Stability and solution structure of complexes with CH3CO-Cys-Ala-Ile-His-NH2, a putative metal binding sequence of histone H3. 754 50

The tyrosine residue present at position 158 in the human O6-alkylguanine-DNA alkyltransferase is one of 22 amino acid residues that are conserved in all known alkyltransferase protein sequences. The importance of this amino acid in the reactions brought about by the alkyltransferase was studied by changing this residue to alanine or to phenylalanine. The control and mutant alkyltransferase proteins were expressed in an Escherichia coli strain lacking alkyltransferase activity and the proteins purified to near homogeneity and their activities measured using both methylated DNA and O6-benzylguanine (BG) as substrates. The alteration to alanine led to a very large decrease in activity towards both substrates but removal of O6-methylguanine from DNA and the conversion of BG to guanine could still be detected when large amounts of the protein were used. The activity of the Y158A mutant was at least 800 times less than that of the control alkyltransferase. The change of tyrosine-158 to phenylalanine reduced the rate of reaction with methylated DNA only slightly (to about one-third). The conversion of BG to guanine by the Y158F mutant was also reduced to about one-third when assayed in the absence of DNA and by about one-half in the presence of DNA. These results suggest that the presence of tyrosine at position 158 plays an important but not absolutely essential role in the reactions brought about by the alkyltransferase. This role is likely to involve the stabilization of the bound substrate by interaction with the aromatic ring of the tyrosine. The hydrogen bond formed by the hydroxyl group from tyrosine-158 may also facilitate the reaction but the contribution from this interaction is relatively small.
Carcinogenesis 1995 Jul
PMID:The role of tyrosine-158 in O6-alkylguanine-DNA alkyltransferase activity. 761 99

Although the human O6-alkylguanine-DNA alkyltransferase (AGT) is very sensitive to inactivation by O6-benzylguanine (BG) or 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine (5-nitroso-BP), the equivalent protein formed by the carboxyl terminal domain of the product of the Escherichia coli ada gene (Ada-C) is unaffected by these inhibitors. This difference is remarkable in view of the substantial similarity between these proteins (33% of the residues in the common sequence are identical) and is potentially very important since these inhibitors are under development as drugs to enhance the anti-tumor activity of alkylating agents. In order to understand the reason for the resistance of the Ada-C protein, we have made chimeras between Ada-C and AGT sequences and mutations in the Ada-C protein, expressed the altered proteins in an E. coli strain lacking endogenous alkyltransferase activity and tested the inactivation of the resulting proteins by BG or 5-nitroso-BP. Chimeric alkyltransferase proteins were made in which the residues on the amino side of the cysteine acceptor site came from Ada-C and the residues on the carboxyl side came from AGT and vice versa but these did not show sensitivity to BG suggesting that resistance is produced by residues in both segments of the protein. Analysis of the Ada-C mutant proteins revealed two sites for mutations that confer sensitivity to these inhibitors. One of these was tryptophan-336 and the other was residues lysine-314 and alanine-316. Thus, when the combined mutations of A316P/W336A were made in the Ada-C sequence, the protein was sensitive to inactivation by BG. This A316P/W336A mutant protein was even more sensitive to 5-nitroso-BP and the mutant proteins W336A, K314P/A316P and A316P could also be inhibited by this drug (in decreasing order of sensitivity) although the control Ada-C and a mutant R335S were not inhibited. These results provide strong support for the hypothesis that the resistance of the Ada-C alkyl-transferase is due to a steric effect limiting access to the active site. Insertion of proline residues at positions 314 and 316 and removal of the bulky tryptophan residue at position 336 increases the space available at the active site and permits these inhibitors to be effective.
Carcinogenesis 1995 Aug
PMID:Mutations in the Ada O6-alkylguanine-DNA alkyltransferase conferring sensitivity to inactivation by O6-benzylguanine and 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine. 763 90

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) was measured as an indicator of nickel-induced oxidative base damage in the presence of H2O2. Heterochromatic proteins isolated from Chinese hamster liver cells enhanced the formation of 8-oxo-dG induced by NiCl2 and H2O2 in vitro, whereas euchromatic proteins inhibited this reaction. The inhibitory effect of euchromatic proteins on dG oxidation may be due to the oxygen radical scavenging effects of low molecular weight protein-rich fractions. Gel electrophoresis confirmed that histone H1 was present at a higher concentration in heterochromatin than in euchromatin. It is believed that the presence of nickel-protein complexes in cells is crucial for the formation of reactive oxygen species (ROS). We found that Ni2+ binds to histone H1 and core histones as determined by 63Ni autoradiography of proteins on nitrocellulose membranes. In vitro studies showed that commercially purified histone H1, and to a considerably lesser extent core histones, enhanced the NiCl2 and H2O2 catalyzed formation of 8-oxo-dG in a reaction containing free dG base. Since histone H1 is a lysine- and alanine-rich protein, the levels of 8-oxo-dG induced by NiCl2 and H2O2 were studied in the presence of these amino acids and found to be enhanced by them. These results suggest that nickel may specifically produce oxidative DNA damage in heterochromatin because of the nature of its binding to histone H1 and core histones. This selective oxidation of genetically inactive heterochromatin may explain why nickel compounds which generate oxygen radicals and oxidize DNA bases are inactive in most gene mutation assays.
Carcinogenesis 1995 Aug
PMID:Heterochromatic proteins specifically enhance nickel-induced 8-oxo-dG formation. 763

To assess the possibility that two conserved amino acids (glutamine 90 and asparagine 137) in O6-methylguanine-DNA methyltransferase (MGMT) are involved in protein-substrate contact and/or discrimination between favored and non-favored substrates, families of proteins mutant at these two sites were expressed in alkyltransferase-deficient bacteria and analyzed for stability, ability to repair O6-methylguanine (MG)-containing DNA, and ability to differentially repair a preferred (MG-containing DNA) versus a non-preferred (free base MG) substrate. All seven proteins mutant at glutamine 90 (except a proline mutant) were stable in bacteria and repaired MG-containing DNA (> 50% of wild-type levels). A representative glutamine 90 mutant protein was not, however, significantly different from the wild-type protein in the preferential repair of MG-containing DNA versus MG free base. Of eight proteins mutant at asparagine 137, only glutamine and serine mutants repaired MG-containing DNA to any degree (8.5% and 0.8% of wild-type respectively) and only the glutamine mutant protein was detectable in bacterial sonicates by Western blot analysis. Alanine and leucine mutant alkyltransferases, inactive and unstable as non-fusion proteins, could, however, be stably expressed in bacteria as glutathione S-transferase fusion proteins, although the proteins were still inactive in repair. These results suggest that while glutamine 90 has no direct role in MG-DNA methyltransferase-mediated repair or free base/lesioned DNA substrate specificity, asparagine 137 is important in both the stability and activity of the protein and may contribute to the formation or function of the active site of the protein.
Carcinogenesis 1994 Sep
PMID:The role of two conserved amino acids, glutamine 90 and asparagine 137, in O6-methylguanine-DNA methyltransferase stability, activity and substrate specificity. 792 83

The effects of combined treatment with NaNO2 and phenolic compounds on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15-20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3-methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3-methoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t-butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4-benzenetriol, dl-3-(3,4-dihydroxyphenyl)-alanine and hydroquinone in combination with NaNO2. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.
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PMID:Effects of combined treatment with phenolic compounds and sodium nitrite on two-stage carcinogenesis and cell proliferation in the rat stomach. 810 88

Mutation of the p53 gene is thought to be a late event in human colorectal carcinogenesis, involved in the malignant conversion of the adenoma to the carcinoma. One of the questions that we hoped to address was whether, in vivo, a single mutational event in one p53 gene is sufficient to confer a significant growth advantage on a colonic epithelial cell. Such a growth advantage could result either from an increase in growth rate and/or loss of response to inhibitory growth signals naturally present in the colonic crypt. We therefore introduced the pC53-SCX3 143 (Val-Ala) p53 mutation into a non tumorigenic adenoma derived cell line, AA/C1, which contained a truncating APC mutation, activating K-ras mutation but was wild-type for the p53 protein. High levels of mutant p53 protein were detected in the pC53-SCX3 transfected AA/C1 cell lines but was found not to affect either the in vitro (colony forming efficiency, anchorage independence) or in vivo (tumorigenicity in nude mice) growth, when compared to vector control or the parental AA/C1 cell line. In addition, to test whether the cells become less sensitive to inhibitory growth factors, the response of the cell lines to the naturally occurring growth inhibitor TGF beta was also investigated. Even though TGF beta had previously been implicated in the control of growth of intestinal epithelium, expression of the mutant p53 protein did not affect the sensitivity of the parental AA/C1 cell line to TGF beta. Under the experimental conditions tested expression of the 143 (Val-Ala) p53 protein was unable to affect the in vitro or in vivo growth characteristics of the adenoma derived AA/C1 cell line. When compared to other studies, these results suggest that the genetic background of the individual recipient cell may greatly influence the effect of expression of a particular p53 mutation.
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PMID:Transfection and expression of mutant p53 protein does not alter the in vivo or in vitro growth characteristics of the AA/C1 human adenoma derived cell line, including sensitivity to transforming growth factor-beta 1. 815 11


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