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)

Karyotype, mitochondrial ultrastructure and several enzymatic activities were studied in two clones, D22 and D27, from SV40-transformed rabbit chondrocytes. Similar chromosome alterations, with recurrent losses and gains were observed at the various passages. Mitochondria were rare, with increase in size and crest alterations. By comparison to non-transformed rabbit chondrocytes, activities of superoxide dismutase 1 and 2 (SOD) and glutathione peroxidase were increased, those of glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase fluctuated according to passages, thymidylate synthase decreased, thymidine kinase and hypoxanthine-phosphoribosyl-transferase increased and the ratio lactate dehydrogenase B/A increased. In most cases, these variations were correlated with the number of chromosomes carrying the genes encoding for corresponding enzymes. These results, compared to those obtained in SV40-transformed human fibroblasts, demonstrate that the two cell types behave differently for detoxication systems against oxygen radicals, in particular for SOD2 activity, and have opposite imbalances of chromosomes carrying the corresponding genes.
Carcinogenesis 1992 May
PMID:Chromosomal, mitochondrial and metabolic alterations in SV40-transformed rabbit chondrocytes. 131 10

Cultured rat liver epithelial cells (RLE) transformed with repeated treatments of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) demonstrate many features of the common biochemical phenotype of multidrug resistance (MDR) seen in vivo in 'resistant hepatocytes'. The cells have increased glutathione-S-transferase placental subunit (GST-Yp), gamma-glutamyltranspeptidase (GGT), glutathione (GSH) and glutathione peroxidase and are resistant to MNNG. Phenotypically identical RLE cells spontaneously transformed by selective culture conditions showed low levels of GGT and GST and were not resistant to MNNG. Both chemical and spontaneous transformants are cross resistant to doxorubicin although resistance is consistently greater in chemical transformants. No direct correlation was found between the degree of resistance to doxorubicin and MDR gene expression in either of the chemically or spontaneously transformed RLE cells. These observations suggest that in chemical carcinogenesis, other mechanisms of drug detoxification are involved and that MDR expression is not a consistent feature.
Carcinogenesis 1992 Sep
PMID:Drug resistance in cultured rat liver epithelial cells spontaneously and chemically transformed. 138 81

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.
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PMID:Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate. 139 88

Induction of glutathione S-transferases (GST) by the anticarcinogen butylated hydroxyanisole (BHA) has been examined in lung, kidney and small intestine of male and female BALB/c mice. BHA produced maximal induction of GST in the gut and although it increased GST levels in the kidney, it had little effect on pulmonary GST. Dietary BHA induced Alpha (Ya and Yk), Mu (Yb) and Pi (Yf) class GST subunits at least 10-fold in the small intestine but, by contrast, selenium-dependent glutathione peroxidase activity was reduced by approximately 4-fold in this organ following BHA treatment. In the kidney, all of the GST subunits, apart from Yk in males, showed modest levels of induction by BHA. However, a pronounced sex difference in the expression of renal alpha class subunits in both control and BHA-treated mice was observed, with female mice expressing approximately 4-fold greater levels of Ya and Yk than male mice. All renal GST were localized primarily in the proximal tubules. Dietary BHA was found to have the least inductive effect in the lung, where the GST were localized solely in the bronchi. The pulmonary Mu class GST subunits were induced approximately 2-fold by BHA; the expression of other GST was marginally increased by this inducer. Alpha class GST was also subject to sexual differentiation in the lung with female mice possessing higher levels of Yc and Yk than males. The Ya-type subunit was not detected in the lung nor was it induced by BHA.
Carcinogenesis 1992 Dec
PMID:Modulation of glutathione S-transferases and glutathione peroxidase by the anticarcinogen butylated hydroxyanisole in murine extrahepatic organs. 147 31

The glutathione transferases, a family of multifunctional proteins, catalyze the glutathione conjugation reaction with electrophilic compounds biotransformed from xenobiotics, including carcinogens. In preneoplastic cells as well as neoplastic cells, specific molecular forms of glutathione transferase are known to be expressed and have been known to participate in the mechanisms of their resistance to drugs. In this article, following a brief description of recently identified molecular forms, we review new findings regarding the respective molecular forms involved in carcinogenesis and anticancer drug resistance, with particular emphasis on Pi class forms in preneoplastic tissues. The rat Pi class form, GST-P (GST 7-7), is strongly expressed not only in hepatic foci and hepatomas, but also in initiated cells that occur at the very early stages of chemical hepatocarcinogenesis, and is regarded as one of the most reliable markers for preneoplastic lesions in the rat liver. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-responsive element-like sequences have been identified in upstream regions of the GST-P gene, and oncogene products c-jun and c-fos are suggested to activate the gene. The Pi-class forms possess unique enzymatic properties, including broad substrate specificity, glutathione peroxidase activity toward lipid hydroperoxides, low sensitivity to organic anion inhibitors, and high sensitivity to active oxygen species. The possible functions of Pi class glutathione transferases in neoplastic tissues and drug-resistant cells are discussed.
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PMID:Glutathione transferases and cancer. 152 61

Treatment of rats with a single carcinogenic dose of CdCl2 (i.e., 30 mumol/kg) caused severe hemorrhagic damage in the testis within the first 12 h after the metal. Subsequently, atrophy with calcification developed in the next 2-3 mo. Atrophied tissues regenerated during the 1 yr after exposure. Twelve hours after exposure to the Cd treatment, lipid peroxidation levels, Fe content, and cellular production of H2O2 were remarkably elevated in testicular Leydig cells, the target cell population for Cd carcinogenesis. At the same time, glutathione peroxidase activity rose, glutathione reductase and catalase activities were reduced, and superoxide dismutase activity was unchanged. Xanthine oxidase activity in Leydig cells was also elevated at 6 and 9 h after the Cd treatment. Reduced glutathione in testes was decreased and oxidized glutathione was increased 12 h after exposure to the metal. These facts suggest that the carcinogenic doses of Cd induced oxidative stress while compromising cellular defense mechanisms against such stress. Therefore, active oxygen species such as H2O2 may have an important role in the initiation of carcinogenesis within the target cell population.
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PMID:Role of oxidative stress in single-dose, cadmium-induced testicular cancer. 152 11

The effects of selenium supplementation on induction of cholangiocarcinomas and related precancerous lesions in female Syrian Golden hamsters by N'-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Four-week-old animals were divided into two groups according to the selenium level contained in the drinking water (0.1 ppm or 4.0 ppm) and fed a purified diet containing less than 0.05 ppm of the trace element. Starting at Week 4 of the experiment, hamsters were administered 10 weekly injections of BOP (10 mg/kg body wt) and then killed 18 weeks after the last carcinogen administration. Animals receiving physiological saline alone served as controls. Cholangiocellular carcinomas tended to be reduced, and putative preneoplastic lesions of cholangiofibrosis were significantly decreased in the high-as opposed to the low-selenium groups in terms of both incidence rate and number per effective animal. The respective high and low selenium values for incidence and number were 24/38% and 0.34/0.66, respectively, for cholangiocarcinomas and 50/89% and 1.21/8.44, respectively, for cholangiofibroses. Proliferation of intrahepatic bile ducts was also significantly inhibited in the high-selenium group along with cyst formation. Biochemical investigation revealed both selenium level and glutathione peroxidase activity to be significantly greater in the high-than in the low-selenium group livers. The results thus suggest that selenium may inhibit BOP-induction of bile duct lesions, possibly via glutathione peroxidase-mediated alteration of carcinogenesis.
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PMID:Inhibition by selenium of intrahepatic cholangiocarcinoma induction in Syrian golden hamsters by N'-nitrosobis(2-oxopropyl)amine. 166 59

A model of liver hyperplastic noduligenesis was induced in rats in vivo by long-term administration of thioacetamide (TAM; 100 mg/kg day i.p.). Three doses of 50 mg/kg of an antitumoral rhodium(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Blood and liver were obtained from either TAM, Rh(III) complex or TAM plus Rh(III) complex-treated rats in order to determine the interaction of both (tumoral and antitumoral) substances with the biochemical pathways related to glutathione redox cycle, enzyme activities involved in the oxidative stress coupled to the NADPH/NADP pair and enzymes related to the mono-oxygenase P450 system. The results showed that TAM induced an imbalance between the activities of glutathione-coupled enzymes. Glutathione reductase activity increased along with the intoxication, while glutathione peroxidase activity decreased. Alterations in the activity of soluble glutathione peroxidase were parallel to those of catalase. These results, together with decreased activities of enzymes related to cytochrome P450 mono-oxygenase system, NADPH cytochrome P450 reductase and NADH cytochrome b5 reductase, suggest that liver cells are not protected against the peroxidative stress produced by chronic administration of TAM. The Rh(III) complex did not produce significant changes in the parameters assayed when administered alone. When this complex was administered to TAM-treated rats, significant restoration of the following activities was observed: those of NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), that of glutathione reductase (NADPH-consuming enzyme), NADPH-cytochrome P450 reductase and total catalase. These results, together with others in previous studies, suggest that the altered liver function induced by chronic administration of TAM can be partially restored by this rhodium complex. The mechanisms by which this complex counteracts the TAM-induced changes have not yet been established.
Carcinogenesis 1991 Feb
PMID:Alterations in hepatic peroxidation mechanisms in thioacetamide-induced tumors in rats. Effect of a rhodium(III) complex. 167 54

The effects of crocetin pretreatment on both hepatic aflatoxin B1 (AFB1)-DNA binding and AFB1 hepatotoxicity in rats has been examined. For these studies, male Wistar rats were treated with AFB1 (2 mg/kg) by i.p. administration, and the different degrees of hepatic damage were revealed by the elevations of levels of serum marker enzymes such as aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and gamma-glutamyltranspeptidase. After pretreatment of the animals with crocetin (2 or 6 mg/kg) daily for three consecutive days, the enzyme elevations were significantly suppressed. This suggested that the crocetin possessed chemopreventive effects on the early acute hepatic damage induced by AFB1. Under these experimental conditions, consistent elevations of hepatic glutathiones (GSH) and activities of glutathione S-transferase (GST) and glutathione peroxidase (GSH-Px) were observed. Crocetin treatment also decreased AFB1-DNA adduct formation in AFB1-treated animals. From these results, we suggest that the protective effect of crocetin on AFB1 hepatotoxicity in rats might be due to the hepatic tissues' defense mechanisms that elevated the cytosol GSH and the activities of GST and GSH-Px.
Carcinogenesis 1991 Mar
PMID:Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. 167 27

Quinone metabolites of catechol estrogens have been postulated to mediate estradiol-induced carcinogenesis. In this study, this postulate was examined by investigating the effect of modulators of quinone metabolism on estradiol-induced tumor incidence in male Syrian hamsters. 2(3)-t-Butyl-4-hydroxyanisol (BHA) and dicumarol which are known to stimulate or inhibit respectively, the activity of quinone reductase, lowered tumor incidence by 33 and 42% respectively (3/9 and 5/12 tumor-free animals/total respectively), from 100% (13/13) observed with 17 beta-estradiol (E2) treatment only. Ebselen, a substance with glutathione peroxidase-like activity, and sodium 2-mercaptoethanesulfonate (Mesna), a cytoprotective thiol-containing agent, were only marginally effective in decreasing the estradiol-induced kidney tumor incidence (3/11 and 4/19 tumor-free animals/total respectively). The lowering of tumor incidence by BHA and dicumarol correlated well with a 40-45% decrease in renal peroxidatic activity of cytochrome P450 in hamsters treated with these substances plus estradiol for 1 month. In addition, these compounds also inhibited the oxidation of diethylstilbestrol to its corresponding quinone in vitro. An influence on quinone reductase or other detoxifying enzymes in chronically treated male Syrian hamsters could not be detected. These data support a mediation of estradiol-induced carcinogenesis by quinones formed by metabolic oxidation of catechol estrogens.
Carcinogenesis 1990 Apr
PMID:Inhibition of estrogen-induced kidney carcinogenesis in Syrian hamsters by modulators of estrogen metabolism. 169 Oct 52


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