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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carcinogen N-hydroxy-1-naphthylamine reacted with nucleic acids and protein under slightly acidic conditions (pH 5) to form covalently bound derivatives with 3 to 20 naphthyl residues/1000 monomer units. The level of binding was in the following order: DNA greater than polyguanylic acid greater than denatured DNA and ribosomal RNA greater than serum albumin greater than transfer RNA greater than polyadenylic acid. Reactions with nucleosides and nucleotides were not detected, and the binding of N-hydroxy-1-naphthylamine to DNA was not inhibited by the addition of nucleosides, nucleotides, methionine, or glutathione. The reaction rates were first order with respect to both DNA and N-hydroxy-1-naphthylamine concentrations. Enzymatic hydrolysis of the DNA containing naphthyl residues yielded 3 nucleoside-arylamine adducts. The major adduct was identified by chemical, ultraviolet, nuclear magnetic resonance, and mass spectrometric analyses as N-(deoxyguanosin-O6-yl)-1-naphthylamine. The other two adducts were identified as 2-(deoxyguanosin-O6-yl)-1-naphthylamine and its decomposition product. Direct evidence for acid-dependent arylnitrenium ion formation was obtained by isotope exchange upon solvolysis of N-hydroxy-1-naphthylamine in acidic H2 18O, and carbocation formation was indicated by the formation of the solvolysis products, 1-amino-2-naphthol and 1-amino-4-naphthol. These studies demonstrated the conversion of a carcinogenic N-hydroxy arylamine to electrophilic arylnitrenium ion and carbocation species that display high selectivity toward macromolecules. The roles of these electrophiles and their macromolecular adducts in the initiation of urinary bladder carcinogenesis through formation of promutagenic lesions in DNA are suggested.
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PMID:Guanyl O6-arylamination and O6-arylation of DNA by the carcinogen N-hydroxy-1-naphthylamine. 2 2

In studies in this and other laboratories, induction of hepatocardinoma by several different chemical carcinogens was enhanced in rats fed diets deficient in lipotropes (choline, methionine, folic acid), amino acids, and niacin, and high in fat. In some cases, specific supplementation with lipotropes blocked carcinogenesis. In studies reported here, specific supplementation of a marginally deficient diet that enhanced carcinogenesis in rats, with the amino acids or lipotropes in which it was deficient, significantly decreased induction of hepatocarcinoma by N-nitrosodiethylamine. Niacin supplementation decreased hepatocarcinoma incidence only slight; the addition of beef fat to an adequate diet did not enhance tumor induction. Rats fed the amino acid- or lipotrope-supplemented diets had an increased incidence of hepatic hemangioendothelial sarcomas, compared to deficient rats or to rats fed the adequate control diet. Methionine was contained in both the amino acid and the lipotrope supplement and probably was responsible for reducing hepatocarcinoma incidence. Methionine has been found to have an anticarcinogenic effect in other studies and also to block the depletion of hepatic folate stores that is induced by N-nitrosodiethylamine. Interactions between carcinogens, S-adenosylmethionine, and folate may be significant in hepatic or other tissue carcinogenesis. One of more hepatic microsomal oxidases were depressed in rats fed any of the high-fat diets but were not correlated with tumor incidence.
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PMID:Reduction of N-nitrosodiethylamine carcinogenesis in rats by lipotrope or amino acid supplementation of a marginally deficient diet. 6 28

Hepatic levels of S-adenosylmethionine (AdoMet), of glutathione, and of the microsomal enzymes p-nitroanisole demethylase and benzo(a)pyrene hydroxylase were measured in male and female rats fed a diet marginally deficient in choline and methionine and void of folic acid (lipotrope deficient) or an adequate diet for 0 to 14 weeks with and without added 2-acetylaminofluorene (AAF). The urinary metabolites of AAF were determined throughout the experimental period. After 2 to 4 weeks of dietary administration, the hepatic AdoMet levels were 43% lower in male rats fed the lipotrope-deficient diet than in male rats fed the lipotrope-adequate diet; no differences were found in hepatic AdoMet of females fed the lipotrope-deficient or lipotrope-adequate diets for 2 to 14 weeks. Administration of AAF to lipotrope-deficient female rats for 2 weeks led to a transient decrease in hepatic levels of AdoMet. The administration of AAF for 2 to 14 weeks did not significantly affect hepatic AdoMet in female rats fed the lipotrope-adequate diet or in male rats fed either diet. Female rats fed the lipotrope-deficient diet and treated with AAF excreted decreased proportions of N-hydroxy-2-acetylaminofluorene and increased proportions of 5-hydroxy-2-acetylaminofluorene in their urine. However, the urine of lipotrope-deficient male rats treated with AAF contained increased proportions of N-hydroxy-2-acetylaminofluorene and decreased levels of 5-hydroxy-2-acetylaminofluorene. The urinary excretion of 7-hydroxy-2-acetylaminofluorene by male and female lipotrope-deficient rats treated with AAF was generally similar to that in lipotrope-adequate rats. The lipotrope-deficient diet did not appear to alter the hepatic levels of glutathione, p-nitroanisole demethylase, or benzo(a)pyrene hydroxylase activity was lower in the livers of lipotrope-deficient male rats treated with AAF for 8 to 14 weeks than in the livers of lipotrope-deficient rats not receiving the carcinogen. The altered metabolism of AAF correlated well with the previously reported effects of a marginal lipotrope deficiency on AAF carcinogenesis.
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PMID:The effects of a marginally lipotrope-deficient diet on the hepatic levels of S-adenosylmethionine and on the urinary metabolites of 2-acetylaminofluorene in rats. 6 17

Mitochondria were isolated from a slow-growing (9618A) and two intermediate-to-fast-growing (5123C, 5123tc) Morris hepatomas and host livers. The mitochondrial proteins were solubilized and fractionated on sodium dodecyl sulfate:polyacrylamide slab gels. One Coomassie blue-stained band was absent or reduced in amount in all tumors relative to host livers. In addition, a major mitochondrial enzyme present in normal liver, carbamyl phosphate synthetase, was missing or greatly reduced in the slow-growing, highly differentiated hepatoma 9618A, a tumor that is considered to be similar to normal liver in many biochemical and morphological respects. Incubation of mitochondria with [35S]methionine and a suitable amino acid incorporation system resulted in labeling of specific mitochondrial proteins. Autoradiography of the slab gels disclosed four prominently labeled fractions and a number of minor fractions. Preparations from hepatoma 5123tc demonstrated two labeled bands that were absent or greatly reduced in host liver. Host liver preparations displayed a minor band that was absent or greatly reduced in hepatoma 5123C. However, no single change in labeling pattern was common to all three tumors, suggesting the absence of a causal relationship between carcinogenesis and mutations in mitochondrial DNA.
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PMID:Differences in total mitochondrial proteins and proteins synthesized by mitochondria from rat liver and Morris hepatomas 9618A, 5123C, and 5123tc. 20 52

Activities of the adenine purine nucleotide cycle enzymes, i.e., adenylosuccinate (SAMP) synthetase, SAMP lyase, and adenosine 5'-monophosphate deaminse, were determined in hepatic tissue of rats fed and/or given injections of 3'-methyl-4-dimethylaminoazobenzene, 4'-methyl-4-dimethylaminoazobenzene, thioacetamide, ethionine, or 2-acetylaminofluorene. SAMP lyase activity showed an early increase in all regimens containing hepatocarcinogens. Adenosine 5'-monophosphate deaminse showed increases with 3'-methyl-4-dimethylaminoazobenzene and thioacetamide but not with ethionine or 2-acetylaminofluorene. SAMP synthetase either was nonresponsive or else showed inhibition to the carcinogens. Increase in SAMP lyase activity was noted as early as 48 to 72 hr following i.p. injections of these carcinogens. The response of SAMP lyase was not duplicated by analogs of carcinogens such as 4'-methyl-4-dimethylaminoazobenzene or methionine. These data imply interaction of active carcinogens with SAMP lyase and to some extent adenosine 5'-monophosphate deaminse or to some mechanism responsible for their synthesis and/or release. This interaction may be a significant component of the initiation phase of carcinogenesis.
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PMID:Effect of hepatocarcinogens on the adenine purine nucleotide cycle during the initiation phase of carcinogenesis. 44 10

The possibility that carcinogens may affect methylase-mediated methylation of replicating DNA was investigated. A system eminently suitable for this purpose is liver regenerating after partial hepatectomy, as one injection of dimethylnitrosamine (DMN) given during the ensuing period of increased DNA synthesis induces hepatocellular carcinoma. Methylation of DNA by DNA methylase normally occurs only in proportion to DNA synthesis. Therefore simultaneous measurements were made of synthesis (incorporation of [14C]adenine into DNA adenine, or of d[5-3H]cytidine into DNA cytosine), and of methylation (incorporation of [methyl-3H]methionine into 5-methylcytosine of DNA) in liver regenerating after partial hepatectomy. After treatment with DMN, the ratio of methylation: synthesis remained within the normal range. Methyl methanesulphonate (MMS), a compound which damages DNA in regenerating liver in a similar but not identical way to DMN and which does not induce tumors in liver even when given after partial hepatectomy, caused an increase in methylation in relation to synthesis. These experiments therefore do not support the view that altered DNA methylase activity is involved in carcinogenesis.
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PMID:Effect of a single treatment with the alkylating carcinogens dimethylnitrosamine and methyl methanesulphonate on liver regenerating after partial hepatectomy. IV. Effect on methylase-mediated methylation of DNA. 47 54

The concentration of S-adenosylethionine in the liver of ethionine-fed rats was increased gradually during the process of carcinogenesis. This increase may have been due to the decreased capacity of the treated rats to acetylate ethionine sulfoxide. Ethionine sulfoxide is considered as the main reserve pool of ethionine for the synthesis of S-adenosylethionine. When the ethionine diet was supplemented by DL-methionine (0.3 to 0.9%), the increase in the concentration of S-adenosylethionine during the period of observation (28 to 150 days) was lower and the acetylation of ethionine sulfoxide was significantly higher. The concentration of the total S-adenosyl compounds in the liver of rats on a diet supplemented with DL-methionine was increased over the concentration of S-adenosylethionine in rats fed ethionine alone, and the S-adenosylethionine portion of this fraction was only about 30% lower. The supplementation of the diet with methionine restored the diurnal oscillation of adenosine 5'-triphosphate in the liver, which had been absent in rats ingesting only ethionine.
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PMID:The influence of DL-methionine on the metabolism of S-adenosylethionine in rats chronically treated with DL-ethionine. 94 14

A previous report using cervical carcinoma cell lines suggests that the inactivation of two tumor suppressor gene products, p53 and pRB, either by complex formation with the E6 and E7 proteins of oncogenic human papillomaviruses (HPVs) or by mutation, may be an important step in cervical carcinogenesis (M. Scheffner et al., Proc. Natl. Acad. Sci. USA, 88: 5523-5527, 1991). The present study was designed to clarify the association between p53 inactivation and infection with oncogenic HPVs in primary carcinomas of human uterine cervix. We examined 36 primary cervical carcinomas for the presence of HPV DNAs by Southern blot analysis with probes specific for HPV-16, -18, -31, -33, -52, -56, and -58. HPV DNA sequences were detected in 19 of 36 tumors: 10 cases with HPV-16; 3 cases with -18; 3 cases with -58; 2 cases with -56; and one case with -52. The presence of HPV-16 and -18 in cervical carcinomas was further reexamined using polymerase chain reaction. HPV DNA sequences were detected in an additional 10 cases: 9 cases with -16 and one case with -18. The inactivation of the p53 gene by allelic loss or by point mutation was also examined. No allelic loss at the polymorphic site in codon 72 of the p53 gene was detected in any of 10 informative cases. Missense point mutations in the highly conserved regions of the p53 gene were demonstrable as single-stranded conformational polymorphisms of polymerase chain reaction-amplified DNA fragments and subsequently identified by direct DNA sequencing. Point mutations were detected in only two cases: one with an ATG----CTG transversion in codon 133 of exon 5, resulting in a Met----Leu substitution, and another with a CGG----TGG transition in codon 248 of exon 7, resulting in an Arg----Trp substitution. Both tumors with point mutations in p53 genes were among 10 tumors which contained a small copy number of HPV-16 DNA sequences (1 copy of HPV/10(1) to 10(5) cells) detectable by polymerase chain reaction amplification but not by Southern blot analysis of genomic DNAs derived from the tumors. None of 19 tumors with a large copy number of HPV DNA sequences detectable by Southern blot analysis (more than 1 copy of HPV/2 to 10 cells) nor any of 7 tumors with undetectable HPV DNA sequences contained p53 gene mutations in the regions examined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection. 132 6

This study examines proto-oncogene hypomethylation in rat livers during the early stages of hepatocarcinogenesis by dietary methyl deprivation in the presence and absence of initiation by diethylnitrosamine (DEN). Male weanling F344 rats were fed a complete diet, or a diet deficient in methionine and choline (MDD). Half the animals in each dietary group were given a single initiating dose of DEN (20 mg/kg). Animals from each of the treatment groups were killed at 1, 3, 8, 16 and 32 weeks, and hepatic DNA was isolated. This DNA was digested with the restriction enzymes MspI and HpaII to determine the extent of methylation of the CCGG sequences in c-Ha-ras, c-Ki-ras and c-fos proto-oncogenes. The results indicate that the administration of the MDD produced hypomethylation of these proto-oncogenes at all times investigated, independent of DEN initiation. The methylation changes in the c-Ha-ras gene increased in intensity throughout the experiment until at 32 weeks they were similar to the patterns seen in both neoplastic and preneoplastic livers of rats fed the deficient diet for 18 months. These results demonstrate that early, selective hypomethylation of some, but not all, CCGG sites occurs in rats undergoing hepatocarcinogenesis by dietary methyl deprivation.
Carcinogenesis 1992 Oct
PMID:The onset of oncogene hypomethylation in the livers of rats fed methyl-deficient, amino acid-defined diets. 133 Mar 45

The immunocytochemical distribution of the cell-surface enzyme dipeptidyl peptidase IV (DPP IV) has been studied in the human breast at the light and ultrastructural level. The presence of the enzyme was demonstrated on the cell membranes of interlobular fibroblasts, whilst intralobular fibroblasts were DPP-IV-negative. A fluorograph, after immunoprecipitation of 35S-methionine-labelled proteins of fibroblasts from primary breast cultures with an anti-serum to DPP IV, demonstrated a band at 135 kDa consistent with the presence of the enzyme. The clear delineation of 2 functionally distinct subpopulations of breast fibroblasts was maintained in benign fibro-adenomas and cystosarcoma phyllodes, both tumour types having growth characteristics of intralobular stroma. This observation has important implications for both normal breast biology and for breast carcinogenesis.
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PMID:Dipeptidyl peptidase IV expression identifies a functional sub-population of breast fibroblasts. 134 21


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