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

Loss of normal functions and gain of oncogenic functions when the p53 tumor suppressor gene is mutated are considered critical events in the development of the majority of human cancers. Human bronchial epithelial cells (BEAS-2B) provide an in vitro model system to study growth, differentiation, and neoplastic transformation of progenitor cells of lung carcinoma. When wild-type (WT) or mutant (MT; codon 143Val-Ala) human p53 cDNA was transfected into nontumorigenic BEAS-2B cells, we observed that (i) transfected WT p53 suppresses and MT p53 enhances the colony-forming efficiency of these cells, (ii) MT p53 increases resistance to transforming growth factor beta 1, and (iii) clones of MT p53 transfected BEAS-2B cells are tumorigenic when inoculated into athymic nude mice. These results are consistent with the hypothesis that certain mutations in p53 may function in multistage lung carcinogenesis by reducing the responsiveness of bronchial epithelial cells to negative growth factors.
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PMID:Mutant p53 can induce tumorigenic conversion of human bronchial epithelial cells and reduce their responsiveness to a negative growth factor, transforming growth factor beta 1. 155 82

O6-Methylguanine-DNA methyltransferase plays an important role in preventing tumor induction. To elucidate the significance of a highly conserved amino acid sequence of methyltransferase protein, amino acid substitutions were introduced by site-directed mutagenesis of cloned cDNA for human methyltransferase and the activity and stability of mutant forms of enzyme were examined. When cysteine-145, to which the methyl transfer occurs, was replaced by other amino acids, all of the mutants isolated showed the methyltransferase-negative phenotype. From one of the negative mutants, methyltransferase-positive revertants were isolated, all of which carried codons for cysteine. Thus the cysteine residue is essential for acceptance of the methyl group and cannot be replaced by other amino acids. Using this negative and positive selection procedure, analyses were extended to other residues near the acceptor site. At the histidine-146 site, four substitutions (phenylalanine, methionine, asparagine and glutamine) exhibited the positive phenotype but the levels of methyltransferase activity in these mutants were low. With valine-148 substitutions there were six types of positive revertants, among which mutants carrying isoleucine, cysteine and alanine showed significantly high levels of methyltransferase activity. Some mutant forms of cDNA were expressed in methyltransferase-deficient human cells, and the results obtained with Escherichia coli cells were confirmed.
Carcinogenesis 1992 May
PMID:Specific amino acid sequences required for O6-methylguanine-DNA methyltransferase activity: analyses of three residues at or near the methyl acceptor site. 158 96

To further understand the molecular mechanisms and the biological indicators of colonic tumorigenesis, the authors examined tyrosine kinase activity in the cytosol and in the particulate fraction of the homogenates of specimens from 20 human colonic carcinomas and compared them with the adjacent normal mucosal tissues. Total protein tyrosine kinase activity could be precisely detected using miniphosphocellulose column purification and a synthetic peptide, Glu-asparagine (Asp)-alanine (Ala)-Glu-tyrosine (Tyr)-Ala-Ala-arginine (Arg)-Arg-Arg-glycine (Gly) (E11-G1), as an artificial substrate. Tyrosine kinase activity of colonic carcinoma and normal mucosa was reduced in the cytosol fraction whereas activity in the particulate fraction was elevated with respect to protein concentration. The average specific activity ratios were 1.95 +/- 0.27 (normal cytosolic/carcinoma cytosolic) and 0.57 +/- 0.01 (normal particulate/carcinoma particulate) for tyrosine kinase activity. Cellular distribution (% cytosol) of tyrosine kinase activity in normal mucosa and in carcinoma varied from 21.0% to 91.2% and from 7.0% to 61.4%, respectively. In nearly all cases the percentage of cytosolic tyrosine kinase activity in carcinoma tissues was lower than in normal tissues. There was no difference due to histologic type or the presence of adenomatous components. A significant decrease of cytosolic tyrosine kinases was correlated with Dukes' Stage A. With advancing Dukes' stage, the average specific activity ratios (normal cytosol/carcinoma cytosol) were decreased. This study indicates that colonic carcinogenesis might be associated with alterations in cellular levels of tyrosine kinase activity and that the average specific activity ratio (normal cytosol/carcinoma cytosol) had a possible correlation with colonic tumor growth.
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PMID:Altered protein tyrosine kinase levels in human colon carcinoma. 198 53

Protease inhibitors have been shown to be effective suppressors of carcinogenesis in vitro and in vivo. For example, the potato-derived chymotrypsin inhibitor 1 (CI-1) suppresses radiation transformation of C3H/10T1/2 cells in vitro. In the current study, we have investigated the interaction of CI-1 with C3H/10T1/2 cells. At the concentrations examined, CI-1 was non-toxic and had no effect on the doubling time or saturation density of these cells. This compound was taken up by these cells in a time dependent manner. Analysis of CI-1 from treated cells on a chymotrypsin affinity column revealed that active inhibitor was present in the cells. Additionally, CI-1, as well as the soybean derived Bowman-Birk inhibitor and chymostatin, blocked the cleavage of the peptide substrate Suc-Ala-Ala-Pro-Phe-MCA by intact C3H/10T1/2 cells. We have previously demonstrated that this substrate will reduce the transformation yield following treatment of cells with ionizing radiation. Our results suggest that CI-1 may inhibit transformation of C3H/10T1/2 cells in vitro by inhibiting the activity of Suc-Ala-Ala-Pro-Phe-MCA hydrolyzing activity in these cells.
Carcinogenesis 1991 Apr
PMID:The interaction of the potato-derived chymotrypsin inhibitor with C3H/10T1/2 cells. 201 29

In the current studies, we have examined the effect of two specific protease substrates, the thrombin substrate Boc-Val-Pro-Arg-MCA and the chymotrypsin substrate Suc-Ala-Ala-Pro-Phe-MCA, on the oncogenic transformation of C3H/10T1/2 cells induced with: (i) 6 Gy of X-radiation and (ii) 4 Gy of X-radiation followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Both substrates reduced radiation transformation while only Suc-Ala-Ala-Pro-Phe-MCA suppressed the TPA enhancement of radiation transformation. We have previously reported that C3H/10T1/2 cells contain at least two proteolytic activities which will cleave these substrates. Our results therefore suggest that: (i) these substrates may inhibit oncogenic transformation due to the fact that they are competitive substrates for these enzymes; and (ii) two or more proteases play an important role in the malignant transformation of these cells.
Carcinogenesis 1990 Feb
PMID:Inhibition of radiation-induced transformation of C3H/10T1/2 cells by specific protease substrates. 240 34

Creatine or one of 15 amino acids were mixed with minced pork before broiling at 200 degrees C. Total mutagenic activity and reversed-phase HPLC-separated mutagenicity profiles were determined for the crust and pan residue of all samples and also in the aerosol fraction of the smoke formed during cooking of the creatine-fortified samples. Addition of 5% (w/w) creatine increased the total mutagenicity 4-fold without changing the mutagenicity profile of either crust, pan residue or aerosol. Amino acid addition (1% w/w) increased the total mutagenicity between 1.5 (lysine) and 43 times (threonine). In most cases the mutagenicity profiles of crust and pan residues were changed by amino acid addition. Dry-heated mixtures of amino acids and creatine were all mutagenic with a 250-fold range between the amino acids. The production of known food mutagens in these mixtures was analyzed by LC-MS of HPLC-fractionated mutagenic peaks. Serine, threonine, phenylalanine, alanine, leucine and tyrosine were all shown to give rise to one of the known food mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-trimethylimidazopyridine (TMIP). Lyophilized and subsequently fried meat patties and a heated powder of lyophilized meat juice were both mutagenic, with mutagenicity profiles similar to the regular meat crust, showing that water is not a prerequisite for mutagen formation in meat. MeIQx, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-di-MeIQx) and PhIP were shown, by LC-MS, to be present in the dry-heated meat juice. It is concluded that creatine and free amino acids are the main reactants of the mutagen-forming reactions that occur during frying of meat. Creatine is probably a necessary part of all of these reactions; what specific compounds are formed in each case therefore depends upon the levels in the meat of certain free amino acids and their interactions with other, as yet unknown, compounds in the meat.
Carcinogenesis 1989 Dec
PMID:Influence of creatine, amino acids and water on the formation of the mutagenic heterocyclic amines found in cooked meat. 259 Oct 18

The activity of 42 cytostatic drugs used for the treatment of human cancer was tested by the initiator tRNA acceptance assay for carcinogens. Of 17 drugs carcinogenic for rodents, 16 (94.1%) gave a positive response in the assay and six (85.7%) out of seven non-carcinogens showed no activity. The predictive value of the test for cytostatics was 91.7%. Treatment of tRNA with several cytostatics resulted in an inhibition of its acceptance for L-methionine. Cyclophosphamide, dibromdulcitol, 5-deoxy-5-fluorouridine and vincristine also inhibited, in addition to this, the charging of unfractionated tRNA from rat liver with L-alanine, L-lysine, L-phenylalanine and L-valine. Some drugs apparently react with the same target nucleoside which is common for all species of tRNA (probably the terminal adenosine residue that is esterified with amino acids). Such compounds do not yield reliable results in the initiator tRNA acceptance assay since this inhibitory effect interferes with the stimulating effect characteristic for carcinogens. However, results of the present study agree well with those obtained earlier with different classes of compounds (N-nitroso compounds, mycotoxins, etc.) and indicate that this newly developed assay may be a useful alternative also for the testing of carcinogenicity of cytostatic drugs.
Carcinogenesis 1989 Aug
PMID:The initiator tRNA acceptance assay as a short-term test for carcinogens. 5. Results with 42 cytostatic drugs. 275 15

This paper describes in vitro studies on the effects of environmental pollutants (SO2/NOx) in biological systems. Basic physical, chemical and biochemical parameters were analyzed to establish the rate of SO2/NOx absorption by the culture medium. It was shown that the pH remains constant for 24 h of exposure to gas concentrations up to 50 p.p.m. The concentration of ions resulting from absorption of each pollutant in the liquid phase is dependent on their concentration in the gas phase and on exposure time. Short exposure times and high gas dosages resulted in similar doses in the medium as long exposure periods and low gas dosages. The activities of a human serum standard (alkaline phosphatase, ALP; aspartate amino transferase, AST; alanine amino transferase, ALT; gamma-glutamyltransferase, gamma-GT; lactate dehydrogenase, LDH) were determined after gaseous exposure to SO2 and NOx. The results revealed a distinct decrease in the activity of LDH after 1, 3 and 5 h exposure to 200 p.p.m. SO2. The effects of the pollutants were assayed in vitro using fetal hamster lung cells (FHLC), rat hepatocytes and the cell line CO60. For the determination of toxic effects, it was shown that the plating efficiency was a more sensitive parameter than the assay for trypan blue exclusion. Toxicity indicated as an increase of LDH leakage was not observed from FHLC in culture. Instead, a decrease of LDH was found following SO2 exposition. This decrease was similar to that observed for the human serum standard. The induction of DNA single-strand breaks was determined as a measure of genotoxic effects. SO2 application decreased the rate of DNA single-strand breaks induced by N-nitroso-acetoxymethyl-methylamine in both FHLC and in rat hepatocytes. SO2 or NOx treatment of CO60 cells for 1 h did not result in the induction of DNA amplification. HSO3- added directly to the medium as the sodium salt, however, distinctly induced the amplification of SV40 DNA. The amplification rates induced by benzo[a]pyrene or dimethylbenzanthracene were neither influenced by SO2, NOx nor HSO3-. An additive effect of HSO3- with either benzo[a]pyrene or dimethylbenzanthracene for this biological parameter was therefore not observed.
Carcinogenesis 1988 Jul
PMID:Effects of SO2 or NOx on toxic and genotoxic properties of chemical carcinogens. I. In vitro studies. 283 97

An in vivo model of liver hyperplastic noduligenesis was induced in rats by long-term administration of thioacetamide (TAM) (50 mg/kg/day i.p.). Three doses of 50 mg/kg of an antitumoral Rh(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Plasma and urine were obtained from either TAM or Rh(III) complex or TAM plus Rh(III) complex treated rats to determine the interactions of both substances with the biochemical parameters related to liver function. The rise in alkaline phosphatase (ALP), leucine aminopeptidase (LAP), gamma-glutamyl transferase (GGT) and the unchanged activities in the aspartate and alanine aminotransferases (AST, ALT) in plasma of TAM-treated rats indicated that the disease induced by this substance can be considered as a chronic obstructive biliary disease with indices of cell proliferation and tumors. The increased concentration of bilirubin both in the plasma and urine of TAM-treated rats suggested liver cholestasis and hepatobiliary obstruction. The very low values of creatinine clearance indicated that there was some degree of kidney failure due to the effect of TAM. The increased concentration of ammonia both in plasma and urine were probably a consequence of the decreased flux in the urea cycle in the liver. The Rh(III) complex alone did not produce significant changes in the plasma enzyme activities. The only significant changes were found in the concentrations of uric acid and ammonia in the urine. When the Rh(III) complex was administered to TAM-treated rats, significant restoration of the following parameters were observed: plasma enzymatic activities, blood bilirubin and ammonia, uric acid and creatinine in the urine and the creatinine clearance. These results suggest that the altered liver function induced by TAM can be restored by Rh(III) complex. The mechanisms by which this complex acts to counteract the TAM-induced changes are not yet established.
Carcinogenesis 1987 Nov
PMID:Effect of a rhodium complex on alterations of hepatic function in thioacetamide-induced hyperplastic noduligenesis in rats. 288 38

N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.
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PMID:N-(Retinoyl)amino acids. Synthesis and chemopreventive activity in vitro. 333 18


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