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)

Prostaglandin H synthase (PHS), an arachidonic acid-dependent peroxidase, has been implicated in the peroxidative activation of carcinogenic aromatic amines in extrahepatic carcinogen target tissues of experimental animals. We have examined the arachidonic acid-dependent activation of [3H]benzidine to DNA-bound products by microsomal preparations from 75 normal human tissues obtained during necessary surgical procedures. For several samples of urinary bladder epithelium, prostatic epithelium, colonic mucosa, and peripheral lung tissue, an arachidonic acid-dependent, microsomal-catalyzed activation of benzidine was observed; and the activity could be inhibited appreciably by indomethacin, a known inhibitor of PHS. Little or no arachidonic acid-dependent activity was detected in human placenta, breast, or liver microsomes or the majority of colon microsomes. Substrate specificity was also examined with purified ram PHS and with human bladder and with active colon preparations. Purified PHS catalyzed the activation of benzidine much greater than 2-naphthylamine, 2-amino-6-methyldipyrido[1,2-alpha:3',2'-d]imidazole greater than 4-aminobiphenyl greater than 2-amino-3-methylimidazo[4,5-f]quinoline greater than 3-amino-1-methyl-5H-pyrido[4,3-b] indole. In comparison, human bladder and colon microsomes catalyzed the activation of benzidine greater than 4-aminobiphenyl, 2-amino-6-methyldipyrido[1,2-alpha:3',2'-d]imidazole, 2-naphthylamine greater than 2-amino-3-methylimidazo[4,5-f]quinoline, 3-amino-1-methyl-5H-pyrido[4,3-b]indole. To confirm the occurrence of PHS antigen in human extrahepatic tissues, an avidin/biotin-amplified competitive enzyme-linked immunoabsorbent assay was developed with purified ram PHS and a commercially available monoclonal antibody known to cross-react with human platelet PHS. The avidin/biotin-amplified enzyme-linked immunosorbent assay, which detected ng quantities of ram PHS, clearly established the presence of the PHS protein in human bladder, prostate, and lung microsomes. In contrast, PHS antigen was not detected in the liver or placental microsomes. The interindividual and tissue-dependent variability of PHS and its role in aromatic amine carcinogenesis are discussed.
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PMID:Arachidonic acid-dependent peroxidative activation of carcinogenic arylamines by extrahepatic human tissue microsomes. 249 73

Aberrant proto-oncogene expression has been implicated in hepatic cell proliferation, transformation and carcinogenesis using a rat model. To investigate the role of ras p21 product expression in human hepatocellular carcinoma (HCC), we have localized ras p21 in formalin fixed, paraffin-embedded normal and abnormal livers utilizing the avidin-biotin peroxidase method and a monoclonal antibody to ras-gene product p21. A semi-quantitative estimate of p21 expression was performed by serial dilutions of primary antibody. While low dilutions of anti-p21 stained normal hepatocytes, higher dilutions failed to react with normal hepatocytes and these dilutions were used for assessment of p21 enhancement. Increased p21 expression of ras oncogene in HCC occurs in fibrolamellar carcinomas and other better differentiated HCC. Tumor dedifferentiation is associated with an attenuation of p21 expression. Liver adjacent to HCC exhibits p21 enhancement, in contrast to liver surrounding metastatic carcinoma, suggesting increased p21 expression in HCC induction.
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PMID:ras oncogene p21 expression in hepatocellular carcinoma. 255 Jun

The formation and repair of carcinogen-DNA adducts in esophagus and liver of rats treated with a single i.p. dose of methylbenzylnitrosamine (MBN), dimethylnitrosamine (DMN), diethylnitrosamine (DEN) or ethylnitrosourea (ENU) has been studied using peroxidase immunocytochemistry to visualize O6-alkylguanine in DNA of individual cells. After MBN O6-methylguanine (O6-MeG) specific nuclear staining was only present in the target tissue for tumor induction, the esophageal epithelium. Part of the adducts persisted for at least 72 h. No O6-MeG could be detected in liver. DEN, a carcinogen in liver and esophagus, led to DNA modification of esophageal epithelial cells, and liver parenchymal and non-parenchymal (Kupffer and sinusoidal) cells of the centrilobular area. O6-EtG was removed within 72 h from both liver cell populations. A similar distribution of adduct (O6-MeG) formation was observed in liver after the hepatocarcinogen DMN, but this nitrosamine did not detectably modify esophageal cells. O6-MeG persisted in Kupffer and especially sinusoidal lining cells of liver, consistent with the induction of sarcomas by DMN. The relatively unspecific, directly alkylating carcinogen ENU modified DNA of all cell types to a similar extent. A qualitative correlation was obtained between the tissue specific ability to induce tumors and the formation of O6-alkylguanine (O6-alkylG). Our experiments support the hypothesis that DNA modification is necessary for the initiation of carcinogenesis by chemical carcinogens, and that a low capacity to repair promutagenic lesions, like O6-alkylG, potentiates this process.
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PMID:Immunocytochemical analysis of O6-alkylguanine shows tissue specific formation in and removal from esophageal and liver DNA in rats treated with methylbenzylnitrosamine, dimethylnitrosamine, diethylnitrosamine and ethylnitrosourea. 266 Sep 79

The cell kinetics of pepsinogen isozyme 1 altered pyloric gland (PAPG) cells with low pepsinogen isozyme 1 (Pg 1) content were analysed using double immunohistochemical staining for bromodeoxyuridine (BrdU) incorporation and Pg 1 in male WKY/NCrj rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After administration of 100 micrograms/ml MNNG for 10 weeks in the drinking water, carcinogenic insult was terminated and the animals killed two weeks later. BrdU was given either as a single i.p. injection (100 mg/kg b.w.) 1 h prior to death or continuously by osmotic minipump (120 micrograms/h) for 4, 7 and 10 days before killing. Immunogold-silver staining was used to detect BrdU and the avidin-biotin-peroxidase complex method adopted for demonstration of Pg 1. PAPG were found only in the MNNG treated group: their frequency was 4.1 +/- 0.6 per 100 pyloric glands. Almost no normal pyloric gland cells with high Pg 1 content demonstrated incorporation after BrdU flash labelling. However, a few pyloric gland cells in PAPG were labelled. The number of labelled cells in the pyloric columns containing PAPG was larger (P less than 0.05) than in normal pyloric columns. After continuous BrdU administration, the life span of cells comprising PAPG was estimated to be approximately 6-8 days while that of normal pyloric gland cells was approximately 11-13 days. Thus, the data indicate that PAPG cells demonstrate a degree of independence from surrounding pyloric glands with regard to proliferation kinetics, suggesting that PAPG is a preneoplastic lesion involved in gastric carcinogenesis.
Carcinogenesis 1989 May
PMID:Proliferation kinetics of pepsinogen altered pyloric gland cells in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine. 270 44

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
Carcinogenesis 1989 Jun
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Diethyldithiocarbamate (DDTC) injected i.p. inhibits remarkably and in a dose-dependent manner 12-O-tetradecanoylphorbol-13-acetate (TPA)-decreased glutathione (GSH) peroxidase and TPA-induced ornithine decarboxylase (ODC) activities in mouse epidermis in vivo. DDTC is more potent in inhibiting these effects of TPA than 16 other antioxidants, free radical scavengers, thiol-containing compounds, and reduced glutathione (GSH) level-raising agents, even though some of these treatments are applied directly to the TPA-treated skin. DDTC also inhibits the effects of several structurally different tumor promoters and the greater GSH peroxidase and ODC responses produced by repeated TPA treatments. The inhibitory effects of DDTC on TPA-decreased GSH peroxidase and TPA-induced ODC activities are additive with those of Na2SeO3 and D-alpha-tocopherol (vitamin E). Interestingly, DDTC is a more effective inhibitor when it is administered after TPA, suggesting that DDTC may supplement, facilitate, and/or enhance the activity of the natural GSH-dependent detoxifying system protecting the epidermis against the oxidative challenge presumably linked to the tumor-promoting activity of TPA. When tested in the initiation-promotion protocols, DDTC inhibits to the same degree complete tumor promotion by TPA and stage 2 tumor promotion by mezerein, in relation with its identical inhibition of the GSH peroxidase and ODC responses to both TPA and mezerein. Moreover, the inhibition of the first stage tumor-promoting activity of TPA by DDTC may be attributed to its ability to inhibit TPA-induced DNA synthesis, a postulated component of the conversion phase of skin carcinogenesis when TPA is used as a stage 1 tumor promoter.
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PMID:Inhibition of multistage tumor promotion in mouse skin by diethyldithiocarbamate. 282 29

The fetal, normal adult, and malignant squamous epitheliums of the cervix were immunohistochemically examined by the avidin-biotin-peroxidase complex method with monoclonal antibodies for blood group antigens (BGAs) A, B, H, Lewis a, and Lewis b. The results were as follows. 1) ABH antigen compatible with ABO status was found in most normal squamous epithelium of fetal and adult cervix. 2) Compatible ABH and A antigen were abolished in small cell nonkeratinizing squamous cell carcinomas (SNKCs) and large cell nonkeratinizing squamous cell carcinomas (LNKCs), respectively. But no remarkable change in ABH antigen expression was observed in other types of cervical lesions. 3) Precursor H antigen was accumulated in all types of malignant lesions. 4) Incompatible expression of A or B antigen was observed in some cases of LNKCs and keratinizing squamous cell carcinomas. 5) Lewis antigens were abolished to various degrees in malignant lesions of the cervix. The present study showed the change in BGAs expression during carcinogenesis of the cervix, but further investigation is needed to elucidate the interaction between these changes in BGAs and the biological behavior of cancer cells.
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PMID:[Expression of blood group antigens A, B, H, Lewis a, Lewis b, in malignant lesions of the uterine cervix]. 283 74

244 cervical tissue specimens with different diagnoses were stained by peroxidase-anti-peroxidase technique (PAP) for assay of the human papillomavirus (HPV) genus-specific antigen, the first of its kind performed in China. HPV antigen was detected in 41.93% of simple condyloma group, in 35.29% of dysplasia with condyloma and in 27.27% of carcinoma with condyloma. There was no positive in the control, dysplasia or carcinoma groups. The antigen positive nuclei were found in the koilocytes or parakeratosis cells in the upper layers of the epithelium. The severer the condyloma, the higher the positive rate of antigen. In the severe condyloma group, the positive rate was as high as 64.71%. The koilocytes were observed in every HPV antigen positive section. In view of the coexistence and continuous transformation of condyloma, dysplasia and carcinoma in pathomorphology, these results provide an important evidence to the further studies on the relation between HPV infection and carcinogenesis of cancer of uterine cervix.
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PMID:[Human papillomavirus infection and carcinogenesis of cancer of uterine cervix. II. Immunoperoxidase localization of papilloma-virus antigen in tissues of the uterine cervix]. 283 40

gamma-Glutamyltranspeptidase (gamma-GT) is known to be increased in putative pre-neoplastic foci but also in the periportal zone I of rat liver under a variety of circumstances not directly related to carcinogenesis. To be able to distinguish between these two instances gamma-GT was studied by enzyme determination in micro-dissections obtained from the two locations and by both histochemical and immunohistochemical staining in serial sections. Altered hepatic foci and alterations in zone I were produced in three models of hepatocarcinogenesis: initiation by N-nitrosomorpholine and tumor promotion by phenobarbital, continuous administration of 2-acetylaminofluorene and continuous administration of methapyrilene hydrochloride. In micro-dissections gamma-GT activity was similarly increased in focal lesions and in zone I after feeding methapyrilene. Histochemically detectable gamma-GT, stained according to Rutenburg et al. (23), was observed both in zone I and in focal lesions. Focal lesions were also ATPase negative and UDP-glucuronyltransferase positive in all three models. gamma-GT in focal lesions could be selectively detected by immunohistochemical staining using antibodies to the rat kidney enzyme and an indirect peroxidase reaction. These findings suggest immunochemical differences between gamma-GT in focal lesions and in zone I.
Carcinogenesis 1986 Sep
PMID:Immunohistochemical differentiation of gamma-glutamyltranspeptidase in focal lesions and in zone I of rat liver after treatment with chemical carcinogens. 287 97

Reduced glutathione (GSH) is mutagenic in Salmonella in the presence of gamma-glutamyltranspeptidase (GGT), with the highest response obtained in strain TA102. Reduced cysteinylglycine, one of the products of GGT metabolism of GSH, is mutagenic in the absence of GGT. In strain TA102, GSH mutagenesis was dependent on molecular oxygen, enhanced by iron, inhibited by EDTA, desferrioxamine mesylate, mannitol, butylated hydroxyanisole, peroxidase and catalase, but not by superoxide dismutase. Binding of GSH or its GGT-dependent metabolites to DNA in vitro was not detected. This is consistent with a model of an indirect mechanism of mutagenesis, i.e. cleavage of GSH by GGT, followed by facile auto-oxidation of the resulting cysteinylglycine, with the production of free radicals which lead to the (pen)ultimate mutagen, H2O2.
Carcinogenesis 1988 May
PMID:Glutathione mutagenesis in Salmonella typhimurium is a gamma-glutamyltranspeptidase-enhanced process involving active oxygen species. 289 53


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