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)

Chloroethylnitrosoureas (CNU) are antitumor agents which produce DNA interstrand crosslinks. We have proposed that crosslinks are produced in DNA via monoadduct formation at the guanine-O6 position, followed by a delayed reaction with the opposite DNA strand. Human cells are known to differ in their capacity to repair the O6-methylguanine lesion. One example of this repair capacity is the ability of cells to reactivate adenovirus which has been damaged by in vitro treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Cells that repair the virus are designated Mer+ and deficient cells Mer-. In a recent report, we showed a clear correlation between CNU-induced DNA interstrand crosslinking and the Mer phenotype. Mer- cells produced consistently higher levels of interstrand crosslinks than did Mer+ cells. In the present study we have measured the CNU-induced DNA interstrand crosslinking in IMR-90 normal human fibroblasts (Mer+), HT-29 human colon carcinoma cells (Mer+), and VA-13 SV-40 transformed human cells (Mer-) following pretreatment with MNNG. Cells were treated for 1 h with MNNG, then for an additional 1 h with CNU. Comparable levels of CNU-induced DNA interstrand crosslinking were observed in all cell lines. This crosslinking has been previously undetected in the IMR-90 and HT-29 cells. Cytotoxicity studies showed that MNNG pretreatment greatly enhanced the killing of IMR-90 and HT-29 cells by CNU, however, in VA-13 cells the increase in cell kill was smaller. These data suggest that in Mer+ cells a DNA repair system may remove chloroethyl monoadducts before the lethal DNA interstrand crosslinks can form. However, pretreatment of cells with MNNG may saturate this repair system rendering it inoperable.
Carcinogenesis 1983
PMID:Pretreatment of normal human fibroblasts and human colon carcinoma cells with MNNG allows chloroethylnitrosourea to produce DNA interstrand crosslinks not observed in cells treated with chloroethylnitrosourea alone. 686 Dec 80

Altered expression of ABH blood group substances is a common feature of human colorectal carcinoma, yet it remains unclear how these structural changes influence the biological properties of tumor cells. Azoxymethane-induced rat colon tumors display many features of the human disease, thereby providing a potentially useful model to study the role of blood group substances in colon cancer progression. We have prepared monoclonal antibodies to a microsomal fraction isolated from an azoxymethane-induced rat colon tumor and selected an antibody that detects cancer-associated changes. Monoclonal antibody (mAb) 3A7 recognizes a determinant on type 2 chain blood group A (GalNAc alpha 1-3[Fuc alpha 1-2]Gal beta 1-4GlcNAc-R) and B (Gal alpha 1-3[Fuc alpha 1-2]Gal beta 1-4GlcNAc-R) oligosaccharides. Expression of the epitope detected by this antibody was developmentally regulated in rat colon, with maximal expression from day 4-21 after birth. Immunohistochemical staining and Western blotting analyses of azoxymethane-induced colon tumors revealed increased expression of the epitope in all of the 21 colonic tumors examined, including preneoplastic glands within transitional mucosa. Conventional and signet-ring adenocarcinomas that had invaded through the muscularis propria (Duke's B2) consistently showed the most intense staining with mAb 3A7, including regions depicting angioinvasion. Some of the lymph node metastases (Duke's C2) stained poorly with the antibody. The epitope was also expressed in blood group A positive human colon carcinoma cell lines, including HT29 and SW480 but not by SW620, a cell line derived from a lymph node metastasis isolated in vivo from the SW480 primary tumor, or in the blood group B cell line SW1417. The glycoproteins detected by mAb 3A7 in rat colon tumors and HT29 cells ranged in size between 50 and 200 kd, including a major species of 140 kd. Affinity chromatography of detergent lysates of normal rat colon on the blood group A specific lectin Dolichos biflorus (DBA)-agarose resulted in nearly quantitative binding of glycoprotein species detected by the antibody. By contrast, immunoreactive glycoproteins from rat colon tumors or HT29 cells bound poorly to DBA-agarose but were retained by another blood group A-binding lectin, Helix-pomatia (HPA)-agarose. These results indicate that colon carcinogenesis results in quantitative as well as qualitative changes in oligosaccharides detected by mAb 3A7 and suggest that the combined use of mAb 3A7 and blood group A-specific lectins may provide a useful tool for early detection of colon cancer.
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PMID:Monoclonal antibody recognizing a determinant on type 2 chain blood group A and B oligosaccharides detects oncodevelopmental changes in azoxymethane-induced rat colon tumors and human colon cancer cell lines. 753 50

Eicosanoids have been implicated in colon carcinogenesis, but their role remains unclear. The levels of PGE2 are elevated in colon cancer tissues and in blood draining colon tumors. The effect of eicosanoids on the proliferation of colonic cells is unknown. We studied the effect of several prostaglandins (PGs) and leukotriene (LT)B4 on the proliferation rate of the human colon adenocarcinoma cell lines SW1116 and HT-29 and of 16,16-dimethyl PGE2 (dmPGE2) on the colon of BALB/c mice. PGs E2, F2 alpha, I2, the methyl ester of PGE2, dmPGE2, and LTB4 (10(-10), 10(-8), 10(-6) M), administered for up to 72 h, stimulated cell proliferation in SW1116 cells and all but PGF2 alpha and PGI2 stimulated proliferation in HT-29 cells. The proliferative effect was time- and concentration-dependent. However, in SW1116 cells the response to PGs was 'bell-shaped', being maximal at 10(-8) M, with the 10(-10) and 10(-6) M concentrations being less effective. In HT-29 cells, the addition of methyl groups to the PGE2 molecule increased the proliferative effect. None of these eicosanoids affected the distribution of these cells in the cell cycle or their rate of programmed cell death (apoptosis). dmPGE2 stimulated 3.6-fold the proliferation of colonocytes in normal BALB/c mice. This was determined by bivariate flow cytometric analysis of the expression of proliferating cell nuclear antigen (PCNA) in virtually pure populations of mouse colonocytes. dmPGE2 did not alter the cell cycle distribution of these cells. We conclude that several PGs as well as LTB4 stimulate the proliferation of human colon carcinoma cells in vitro, while dmPGE2 has a similar effect on mouse colonocytes in vivo. These findings raise the possibility that eicosanoids may contribute to colonic carcinogenesis by stimulating the proliferation rate of tumor cells in the colon.
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PMID:Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. 754 86

nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor beta 1 (TGF beta 1) signal transduction. In an earlier study we decreased nm23 mRNA levels 2- to 8-fold by antisense phosphorothiolated oligonucleotides in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGF beta 1. Only TGF beta 1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility. HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23 mRNA levels, while HD3 cell motility was conversely decreased by TGF beta 1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGF beta 1 or TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGF beta 1 and 5-fold by TGF alpha, but not by scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of proteases or modulation of their levels by TGF beta 1. Both HD3 and U9 cells displayed equal levels of urokinase activity and mRNA, equal expression of the metalloproteinase inhibitor TIMP-1, and no detectable collagenases by zymography. No differential response to TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.
Carcinogenesis 1995 Sep
PMID:Colon carcinoma cells with inactive nm23 show increased motility and response to motility factors. 755 87

The genetic changes of cyclin A, DI, E and CDK2 were examined in human colorectal carcinomas by Southern-blot analysis. Gene amplification of cyclin E was detected in 5 of 53 (9.4%) primary colorectal carcinoma tissues. Interestingly, in 3 of 5 tumors showing cyclin E gene amplification, the CDK2 gene was amplified simultaneously with rearrangements. No obvious correlation was detected between gene amplification and clinicopathological features of colorectal carcinomas. Out of 7 colon carcinoma cell lines, 2 showed gene amplification of cyclin E without gene amplification of CDK2. No amplification of cyclin A or DI gene was found in any of the colorectal carcinoma tissues or colon carcinoma cell lines. Our results suggest that the concurrent amplification of cyclin E and CDK2 genes may play a role in colorectal carcinogenesis.
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PMID:Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. 760 62

The tumor suppressor p53 plays a central role in the cellular responses to genotoxic stress. Besides its well known role in activation of the G1 checkpoint after exposure to agents like ionizing radiation and its role in apoptosis, the possibility exists that p53 may have additional roles, such as in DNA repair. For example, p53, is known to bind to single strand DNA such as would occur during repair events, and the proteins encoded by two p53-regulated genes have previously been found to bind to at least one protein involved in DNA damage processing including nucleotide excision repair (NER). NER is an important and versatile DNA repair mechanism, which is the major pathway for repair of u.v.-type lesions and damage by a variety of important carcinogens and mutagens. If components of the p53 pathway are involved in NER, then disruption of p53 function by mutations or expression of certain viral proteins could have important implications in carcinogenesis and cancer treatment. In the present study we show that disruption of normal p53 function in human colon carcinoma RKO cells with either the human papillomavirus E6 oncoprotein or a dominant-negative mutant p53 transgene results in reduced repair of u.v.-induced DNA damage. The E6 and mutant p53-containing cell lines demonstrated reduced repair of u.v.-induced DNA lesions in host cell reactivation experiments with reporter plasmids, and reduced repair in in vitro DNA repair assays. With this in vitro assay, extracts from the E6- and mutant p53-containing lines also showed loss of induced repair following cellular u.v.-irradiation. The reduced DNA repair activity of the transfected cell lines also correlated with reduced clonogenic survival following u.v.-irradiation. These results indicate that p53 and/or p53-regulated gene products function in the NER pathway and that this process is inducible by DNA damage.
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PMID:Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. 770 Jun 29

To study the mutator phenotype characteristic of tumors showing widespread replication errors at simple DNA repeat sequences (RER+), we designed a selectable reporter system for the detection of such mutations in mammalian cells. A hygromycin B phosphotransferase gene was rendered out-of-frame by the insertion of a (CA)13 dinucleotide repeat tract immediately following the ATG start codon, and subcloned into a retroviral expression vector containing a G418 (neo) selectable marker. Following transduction of this construct into cultured cells, clonal neo+ cell lines were established and then tested for their ability to form colonies in hygromycin B-containing medium. Using this system, we found that the HCT116, LS174T and LS180 human colon carcinoma cell lines acquire hygromycin resistance (hygr) at a 100-fold higher frequency than the HT29, SW480, DLD-1 and HCT15 human colon carcinoma and NIH3T3 fibroblast cell lines, and at a 25-fold higher rate than the Rat 6 embyro fibroblast cell line. DNA sequence analysis indicated that frameshift mutations had occurred within the CA dinucleotide repeat tract in HCT116 cells that became hygr. Thus, the mutation rates at simple repeated sequences in mammalian cell lines can be readily determined and studied using this system.
Carcinogenesis 1995 May
PMID:Design of a selectable reporter for the detection of mutations in mammalian simple repeat sequences. 776 88

The levels of expression of phosphoinositide-specific phospholipase Cs (PLCs) were examined in a series of primary human colon carcinomas and in eight colon carcinoma cell lines by using monoclonal antibodies and cDNA probes for PLC gamma 1, PLC beta 1, and PLC delta 1. Western and northern blot analyses of PLC gamma 1 revealed elevated expression of this isozyme at both the protein and mRNA levels in most tumors when compared with paired adjacent normal mucosa samples (in 11 of 13 pairs in the western blots and 8 of 9 pairs in the northern blots). On the other hand, decreased levels of the PLC delta 1 protein were seen in most colon carcinomas (12 of 13 paired samples). The levels of PLC beta 1 protein were too low to detect possible differences between the carcinoma and normal mucosa samples. Relatively high expression of PLC gamma 1 was found in almost all of the eight human colon carcinoma cell lines at both the protein and mRNA levels. Only weak expression of PLC beta 1 was detected in these cell lines, by both western and northern blot analyses, and PLC delta 1 protein was not detected in any of the carcinoma cell lines. These findings provide evidence that colon carcinomas display altered expression of individual isoforms of PLCs and suggest that increased expression of PLC gamma 1 may play an important role in colon carcinogenesis.
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PMID:Expression of phospholipases gamma 1, beta 1, and delta 1 in primary human colon carcinomas and colon carcinoma cell lines. 789 68

The in vitro experiment was carried out following 32P-postlabeling analysis to determine the DNA-reactive bile acids present in the human body. The unconjugated and conjugated forms of cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA) and lithocholic acid (LCA) were added to calf thymus DNA followed by 1 h of incubation at 37 degrees C. After the incubation the mixture was analyzed by the nuclease P1 modification of 32P-postlabeling. Among the 12 bile acids tested, our results showed that unconjugated CDCA and LCA and the glycine and taurine conjugates of LCA (g-LCA, t-LCA) were able to bind covalently with naked DNA in vitro without intervention of any catalyst. It was also shown that bile acid alone did not give any spot on TLC. These binding reactions depended on the bile acid concentration in a linear manner. The data on the extent of binding at a concentration of 0.1 mg/ml showed values of 28.5 (t-LCA), 23.7 (g-LCA), 3.47 (LCA) and 1.32 (CDCA) adducts per 10(8) nucleotides. These reactive bile acids were also incubated with COLO 205 human colon carcinoma cells and Hep G2 human hepatocellular carcinoma cells for 24 h, but no specific DNA adduct was formed. Further, when LCA or CDCA was administered into male Fischer 344 rats by gavage at a dose of 10 mg/rat every 8 h for 3 days, no specific DNA adduct was detected in their liver or colon. Covalent DNA adducts are believed to cause alteration of the primary structure of genes, which is potentially linked to carcinogenesis. Though our preliminary data failed to detect any bile acid-related DNA adducts in the cultured cells or in rats, the results may provide a basis for assuming some of these bile acids to be potential initiators of colon cancer.
Carcinogenesis 1994 Sep
PMID:In vitro formation of DNA adducts with bile acids. 792 85

The presence of several covalent DNA adducts in the human colon was demonstrated by 32P-postlabeling in a previous study. We demonstrated that DNA of all the colonic mucosa tested were selectively adducted by a single genotoxic agent and this modification was completely absent in the DNA of muscular layers. In this study, the DNA adducts of the small intestine are compared with those of the colon to understand the role of mucosa-specific DNA adduct (MSA) in intestinal carcinogenesis. The mucosal DNA of the small intestine from 19 adults undergoing surgery due to gastric carcinoma (seven cases), pancreatic carcinoma (four cases), colon carcinoma (four cases), small intestinal tumor (two cases), intestinal trauma (one case) and ectopic pancreas (one cases) were analyzed. The mucosa-adjacent muscular layer DNA of the corresponding samples was examined as a control. Several common DNA adducts were observed in both mucosal and muscular layers of all the adults. Besides these common background DNA adducts, two MSAs (Si1, Si2) were detected in most of the adults as in colon cases. Si1 was present in all adults examined (19/19 cases) at a level of 0.04-0.22 adducts/10(8) nucleotides (average 0.09) and Si2 was found in 13/19 patients at a level of 0.03-0.08 adducts/10(8) nucleotides (average 0.05). Si2 was the same adduct detected in the adult colonic mucosa. However, they were absent in the adjacent muscular layer as well as in the neonatal intestine tested as a control. The total level of the mucosa-specific DNA adducts of the small intestine was approximately 28-fold lower than that of the colon. Considering that the incidence of cancer in the small intestine is rather lower than that in the colon, these results may be relevant to the development of human intestinal cancer.
Carcinogenesis 1994 Nov
PMID:Mucosa-specific DNA adducts in human small intestine: a comparison with the colon. 795 26


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