Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Humans are continuously exposed to naturally occurring and industrial xenobiotics in their daily lives. Heterocyclic amines, which are formed during the cooking of proteinaceous foods, have been categorized as a new class of naturally occurring xenobiotics. They are divided into 2-amino-3-methylimidazo[4,5-f] quinoline (IQ)- and non-IQ-types. The amounts and proportion of total mutagenicity contributed by the IQ-type heterocyclic amines in cooked food are greater than those of the non-IQ-types. Precursors of the IQ-type heterocyclic amines including IQ, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are creatinine, amino acids and sugars in meat and fish. Both types of heterocyclic amines are carcinogenic in mice and rats. All heterocyclic amines except PhIP frequently induce cancers in the liver, while PhIP induces lymphomas in mice and carcinomas of the colon and mammary gland in rats. Based on quantitative analysis of heterocyclic amines in cooked food and levels of excretion of unchanged heterocyclic amines in human urine, total heterocyclic amine intake was calculated to be around 0.4-16 micrograms/person per day. As in the case of other naturally occurring xenobiotics, and degree of exposure is small and is presumably insufficient alone to account for the development of human cancer. Nevertheless, a linear relationship has been demonstrated between DNA adduct levels and a wide range of doses of MeIQx in animals. In addition, combined treatment with five heterocyclic amines yielded additive or synergistic effects in the development of glutathione S-transferase placental form (GST-P) positive foci. Taking these results and current observations of multiple genetic alterations in human cancers into consideration together, heterocyclic amines are probably involved in the development of human cancer in the presence of other carcinogens, tumor promoters and factors stimulating cancer progression.
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PMID:Heterocyclic amines produced in cooked food: unavoidable xenobiotics. 213 81

We have shown previously that overexpression of p-170 glycoprotein-mediated multidrug resistance plays only a minor role in conferring chemoresistance to human melanoma cells. In addition to membrane transporters like p-170, metabolizing enzyme systems have been implicated in altered drug sensitivity. Recently, glutathione and associated enzymes have been associated with resistance to alkylating substances, particularly in gastrointestinal and gynecologic cancers. In this study, we investigated whether increased levels of glutathione and related enzymes may play a role in chemoresistance in melanoma. Levels of glutathione, glutathione S-transferase (GST), glutathione reductase, and gamma-glutamyl transpeptidase were analyzed in melanoma and non-melanoma cell lines. In addition, 18 melanoma metastases derived from skin and lymph nodes were examined. Levels of gamma-glutamyl transpeptidase were statistically different in cells derived from melanocytic tumors compared with non-melanoma cell lines and normal cells. In addition, GST levels in metastases derived from skin or lymph nodes were significantly lower than those in permanent cell lines. However, levels of glutathione and related enzymes in metastases and cell lines fluctuated over a wide range, up to 40-fold, regardless of treatment status or origin of metastases. In a second part of the study, the expression of GST isoenzymes alpha, mu, and pi was studied by immunohistology in 10 benign nevi, 29 primary melanomas, and 39 melanoma metastases before and during chemotherapy. Expression of GST isoenzymes was increased with tumor progression, and GST pi was the strongest isoform expressed. However, no correlation was found between GST levels by immunohistochemistry and the course of tumor progression, between GST levels in metastases obtained before or during chemotherapy, or between GST levels and clinical response. These data suggest that alterations in glutathione metabolism and the expression of GST do not play a major role in resistance to chemotherapeutic drugs in melanoma.
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PMID:Glutathione and related enzymes in tumor progression and metastases of human melanoma. 761 63

Serial magnetic resonance imaging (MRI) was used to evaluate the influences of dietary deoxycholic acid (DCA) on the rate of progression of chemically induced hepatocellular neoplasms in rats. Male Fischer-344 rats with established persistent hepatocellular nodules generated by the Solt-Farber protocol were exposed to dietary DCA (0.3%) between 6 and 12 mo of age. Growth of nodules and carcinomas in vivo was measured by morphometric quantification of tumor images obtained every 6 wk. The final stages of neoplastic progression were determined by terminal histopathological examination and by expression and functional evaluation of glutathione S-transferase (GST) isoenzyme phenotypes. Dietary DCA increased the number of hepatocellular neoplasms per rat, accelerated the rate of growth of persistent nodules, and increased the histological progression of liver tumors. Expression of immunoreactive GST subunits Yf, Ya, and Yb1 was induced in early persistent nodules, a pattern that was maintained throughout the study in both basal diet and DCA-fed groups. However, 5% of early nodules and about 75% of advanced neoplasms were partially or completely deficient in GST Yb2 expression in both groups. DCA did not alter the cytosolic activity for the GST substrates 1-chloro-2,4-dinitrobenzene (CDNB) or trans-4-phenyl-3-buten-2-one (tPBO) in tumors or surrounding liver. However, in both groups, CDNB activity was increased in the tumors relative to the surrounding nonneoplastic tissue, whereas activity for tPBO, a substrate more specific for the Yb2 subunit, was reduced in the tumors. All advanced neoplasms were similarly more resistant than surrounding liver to DNA-binding metabolites of aflatoxin B1 or benzo[a]pyrene. These data demonstrate that DCA can increase the progression of established hepatocellular nodules to larger, more advanced neoplasms but does not preferentially select for a specific GST phenotype. Preferential loss of constitutively expressed GST Yb2 in both basal diet and DCA-fed groups may be an important aspect of progression from resistant nodules to advanced cancers in this model. These studies also demonstrate that serial MRI is a useful tool for measuring the rates of enlargement and patterns of growth in established hepatocellular neoplasms.
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PMID:Influences of dietary deoxycholic acid on progression of hepatocellular neoplasms and expression of glutathione S-transferases in rats. 773 75

We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (pi-class), Ya (alpha-class) and Yb1 (mu-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinity-purified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for trans-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for 1-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive mu-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S-transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S-transferase isoenzymes containing this subunit.
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PMID:Reduced expression of glutathione S-transferase Yb2 during progression of chemically induced hepatocellular carcinomas in Fischer 344 rats. 802 Aug 84

We have identified and characterized a novel human cysteine proteinase of the papain family. A full-length cDNA for this enzyme was cloned from a human brain cDNA library. Nucleotide sequence analysis revealed that the isolated cDNA codes for a polypeptide of 303 amino acids, tentatively called cathepsin Z, that exhibits structural features characteristic of cysteine proteinases. Fluorescent in situ hybridization experiments revealed that the human cathepsin Z gene maps to chromosome 20q13, a location that differs from all cysteine proteinase genes mapped to date. The cDNA encoding cathepsin Z was expressed in Escherichia coli as a fusion protein with glutathione S-transferase, and after purification, the recombinant protein was able to degrade the synthetic peptide benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin, used as a substrate for cysteine proteinases. Northern blot analysis demonstrated that cathepsin Z is widely expressed in human tissues, suggesting that this enzyme could be involved in the normal intracellular protein degradation taking place in all cell types. Cathepsin Z is also ubiquitously distributed in cancer cell lines and in primary tumors from different sources, suggesting that this enzyme may participate in tumor progression as reported for other cathepsins. Finally, on the basis of a series of distinctive structural features, including diverse peptide insertions and an unusual short propeptide, together with its unique chromosomal location among cysteine proteinases, we propose that cathepsin Z may be the first representative of a novel subfamily of this class of proteolytic enzymes.
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PMID:Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. 964 40

A cDNA encoding a new cysteine proteinase belonging to the papain family and called cathepsin F has been cloned from a human prostate cDNA library. This cDNA encodes a polypeptide of 484 amino acids, with the same domain organization as other cysteine proteinases, including a hydrophobic signal sequence, a prodomain, and a catalytic region. However, this propeptide domain is unusually long and distinguishes cathepsin F from other proteinases of the papain family. Cathepsin F also shows all structural motifs characteristic of these proteinases, including the essential cysteine residue of the active site. Consistent with these structural features, cathepsin F produced in Escherichia coli as a fusion protein with glutathione S-transferase degrades the synthetic peptide benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin, a substrate commonly used for functional characterization of cysteine proteinases. Furthermore, this proteolytic activity is blocked by trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, an inhibitor of cysteine proteinases. The gene encoding cathepsin F maps to chromosome 11q13, close to that encoding cathepsin W. Cathepsin F is widely expressed in human tissues, suggesting a role in normal protein catabolism. Northern blot analysis also revealed a significant level of expression in some cancer cell lines opening the possibility that this enzyme could be involved in degradative processes occurring during tumor progression.
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PMID:Molecular cloning and structural and functional characterization of human cathepsin F, a new cysteine proteinase of the papain family with a long propeptide domain. 1031 84

A cDNA encoding a new member of the membrane-type (MT) matrix metalloproteinase (MMP) family has been identified and cloned from a human brain cDNA library. The isolated cDNA encodes a polypeptide of 645 amino acids that displays a similar domain organization as other MMPs, including a predomain with the activation locus, a zinc-binding site, and a hemopexin domain. The deduced amino acid sequence contains a COOH-terminal extension, rich in hydrophobic residues and similar in size to the equivalent domains identified in MT-MMPs. Immunofluorescence and Western blot analysis of COS-7 cells transfected with the isolated cDNA revealed that the encoded protein is localized in the plasma membrane. On the basis of these features, this novel human MMP has been called MT5-MMP because it represents the fifth member of the MT-MMP subfamily of MMPs. Fluorescent in situ hybridization experiments showed that the human MT5-MMP gene (MMP-24) maps to 20q11.2, a region frequently amplified in tumors from diverse sources. Northern blot analysis demonstrated that MT5-MMP is predominantly expressed in brain, kidney, pancreas, and lung. In addition, MT5-MMP transcripts were detected at high levels compared to normal brain tissue in a series of brain tumors, including astrocytomas and glioblastomas. The catalytic domain of MT5-MMP, produced in Escherichia coli as a fusion protein with glutathione S-transferase, exhibits a potent proteolytic activity against progelatinase A, leading to the generation of the Mr 62,000 active form of this enzyme. These data suggest that MT5-MMP may contribute to the activation of progelatinase A in tumor tissues, in which it is overexpressed, thereby facilitating tumor progression.
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PMID:Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. 1036 75

We have developed an in vitro model to study the molecular mechanisms of tumor progression. Using repeated treatments with ionizing radiation or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we caused malignant progression of a papilloma producing mouse keratinocyte cell line, 308 cells. In a previous study we have shown that the malignant variants of 308 cells have elevated reactive oxygen species (ROS) levels, and have established a functional role for the pro-oxidant state in the progressed phenotype (Carcinogenesis 20 (1999) 2063). In this study, we have evaluated the status of intracellular defense mechanisms for ROS scavenging in the progressed phenotype to identify sources that contribute to their pro-oxidant state. Our results demonstrate that a reduction in several anti-oxidant defense mechanisms, including catalase and glutathione S-transferase mu, correlates with the emergence of the malignant phenotype. We provide evidence that attenuation of catalase activity may play a functional role in the malignant progression of mouse keratinocytes.
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PMID:Attenuation of catalase activity in the malignant phenotype plays a functional role in an in vitro model for tumor progression. 1159 85

Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GST delta serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O(6)-alkylguanine in DNA leads to very high rates of G:C deltaA:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by over-riding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.
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PMID:Cancer and phase II drug-metabolizing enzymes. 1257 Jul 45

Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated that DCA exhibits hepatocarcinogenic effects in rodents when administered in drinking water. This chemical does not appear to be highly mutagenic, and the mechanism(s) involved in DCA induction of cancer are not clear. The present work was aimed at identifying changes in gene expression which may indicate critical alterations/pathways involved in this chemical's carcinogenic activities. We used cDNA microarray methods for analyses of gene expression in livers of mice treated with the tumorigenic dose of 2 g/l DCA in drinking water for 4 weeks. Total RNA samples obtained from livers of the control and DCA-treated mice were evaluated for gene expression patterns with Clontech Atlas Mouse 1.2 cDNA and Atlas mouse stress/toxicology arrays, and the data analyzed with AtlasImage 2.01 and one-way ANOVA in JMP4 software. From replicate experiments, we identified 24 genes with altered expression, of which 15 were confirmed by Northern blot analysis. Of the 15 genes, 14 revealed expression suppressed two- to five-fold; they included the following: MHR 23A, cytochrome P450 (CYP) 2C29, CYP 3A11, serum paraoxonase/arylesterase 1 (PON 1), liver carboxylesterase, alpha-1 antitrypsin, ER p72, glutathione S-transferase (GST) Pi 1, angiogenin, vitronectin precursor, cathepsin D (CTSD), plasminogen precursor (contains angiostatin), prothrombin precursor and integrin alpha 3 precursor (ITGA 3). An additional gene, CYP 2A4/5, had a two-fold elevation in expression. Further, in ancillary Northern analyses of total RNA isolated from DCA-induced hepatocellular carcinomas (from earlier reported studies of mice treated with 3.5 g/l DCA for 93 weeks), many of the same genes (11 of 15) noted above showed a similar alteration in expression. In summary, we have identified specific genes involved in the functional categories of cell growth, tissue remodeling, apoptosis, cancer progression and xenobiotic metabolism that have altered levels of expression following exposures to DCA. These findings serve to highlight new pathways in which to further probe DCA effects that may be critical to its tumorigenic activity.
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PMID:Altered gene expression in mouse livers after dichloroacetic acid exposure. 1264 86


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