Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of diamides and diamines were synthesized using 6-amino chrysene and 1-amino pyrene as starting materials. A structure activity study with cis-platinum as internal control against animal and human tumor lines was carried out in vitro. This study indicated that the in vitro cytotoxicity toward these lines depends on the functionality present in the molecules. The diamino compounds were found to be more potent than the diamides, and these were equally active irrespective of the end heterocyclic group, whereas the activity of the diamides was strongly dependent on the terminal unit. In general, the diamides containing chrysene as the chromophore were more active than those with a pyrene ring. The size of the end heterocyclic ring, along with the nature of the spacer connecting the polycyclic ring to the heterocyclic ring, seemed to affect the biological activity in certain cell lines. Hemolysis experiments on a lead compound established that it had activities similar to those described for membrane-stabilizing agents. This agent also demonstrated the capacity to produce differentiation in leukemia cell lines.
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PMID:Polycyclic aromatic compounds as anticancer agents: structure-activity relationships of chrysene and pyrene derivatives. 1131 May 93

Heat shock proteins (hsp) are a highly conserved group of proteins that are synthesized as a response to different forms of stress (heat, toxic chemicals, diseases, non-physiological pH changes). Because of their high sensitivity to changes in the environment, these proteins were suggested as possible early biomarkers of exposure in ecotoxicological studies. The purpose of the present study was to check the suitability of hsp 32 and hsp70 as biomarkers of in vitro exposure to environmentally relevant carcinogens: polycyclic aromatic hydrocarbons (PAHs), their nitro-derivates, aromatic amines, acrylonitrile (ACN) and the mixture of organic compounds adsorbed onto ambient airborne particles (extractable organic matter, EOM). The expression of hsp 32 and hsp70 was studied in human diploid lung fibroblasts (HEL cells) and human monocytic leukaemia cells (THP-1 cells) incubated in vitro with different concentrations of dibenzo[a,l]pyrene (DB[a,l]P), 1-nitropyrene, (NP), 4-aminobiphenyl (ABP), ACN and EOM for different periods of time. The incubation of cells with DB[a,l]P, NP, ABP and EOM did not result in increased levels of hsp 32 or hsp70, either in dose- or time-dependent manner. ACN induced the expression of hsp 32 as well as hsp70 in HEL and THP-1 cells, which probably reflects its ability to induce oxidative stress. We conclude that hsp 32 and hsp70 are not suitable biomarkers of an early exposure to PAHs, their nitro-derivates, aromatic amines or EOM under the conditions used.
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PMID:Heat shock proteins hsp32 and hsp70 as biomarkers of an early response? In vitro induction of heat shock proteins after exposure of cell culture to carcinogenic compounds and their real mixtures. 1464 59

We studied comparative expression and activity of cytochrome P450 family 1 (CYP1) isoforms in rat embryo cells, both primary and immortalized by Rausher leukemia virus (RLV). In RLV-infected embryonal cells compared with the initial ones the expression levels of CYP1A1 and 1B1 mRNAs and benzo[a]pyrene (BP) hydroxylase activity were higher, regardless of their treatment with the CYP1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The sensitivity to BP and 7,12-dimethylbenzo[a]anthracene was higher in the cells immortalized with RLV. The expression level of mRNAs of induction-mediating proteins aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator was the same in both cell cultures tested. Higher sensitivity of cells immortalized with RLV compared with the initial embryo cells to transforming effect of BP, which was described previously, is possibly associated with elevated expression of CYP1 isoforms.
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PMID:Cytochrome P-450 family 1 in rat embryo cell culture immortalized by Rausher leukemia virus. 1506 98

Pifithrin alpha (PFTalpha) is a chemical compound that inhibits p53-mediated gene activation and apoptosis. It has also been recently shown to alter metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs). This has led us to examine the effect of PFTalpha on the activity of cytochrome P-450 (CYP) 1 isoforms, known to metabolize PAHs, such as benzo(a)pyrene (BP), into mutagenic metabolites. We report that PFTalpha caused a potent inhibition of CYP1-related activity as measured by ethoxyresorufin O-deethylase activity in CYP1-containing MCF-7 cells and liver microsomes. It also directly affected the catalytic activity of human recombinant CYP1A1, CYP1A2 and CYP1B1 isoforms, with a potent inhibitory effect towards CYP1B1. The nature of this CYP1B1 inhibition by PFTalpha was mixed-type with an apparent K(i) of 4.38 nM. Blockage of CYP1 activity by PFTalpha was associated with a decreased metabolism of BP, a reduced formation of BP-derived adducts and a diminished BP-induced apoptosis in human cultured cells targets for PAHs like primary human macrophages and p53-negative KG1a leukaemia cells. These data further substantiate an unexpected and p53-independent action of PFTalpha for preventing toxicity of chemical carcinogens such as PAHs, through inhibition of CYP1 enzyme activities, especially that of CYP1B1.
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PMID:Potent inhibition of carcinogen-bioactivating cytochrome P450 1B1 by the p53 inhibitor pifithrin alpha. 1625 75

Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR(b-1/d), responsive) mice were crossed with strain 129S1/SvIm (AHR(d/d), nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, beta-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults.
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PMID:In utero exposure of mice to dibenzo[a,l]pyrene produces lymphoma in the offspring: role of the aryl hydrocarbon receptor. 1642 6

Pro-carcinogens, such as benzo[a]pyrene (B[a]P), that are exogenous ligands of the aromatic hydrocarbon receptor may influence the susceptibility of target-cell populations through the up-regulation of cytochrome P450 (CYP) mixed function oxidases. We examined whether the growth kinetics of MCF-7 cells might determine the level of up-regulation of CYP1A1, CYP1A2 or CYP1B1 by B[a]P, and whether this could then influence subsequent levels of DNA damage. Cell cultures manipulated to be G(0)/G(1)-phase concentrated, S-phase concentrated or G(2)/M-phase concentrated were treated with B[a]P and the expression levels of CYP1A1, CYP1A2, CYP1B1, cyclin-dependent kinase inhibitor 1A [CDKN1A (P21(WAF1/CIP1))], B-cell leukaemia/lymphoma-2 (BCL-2), and Bcl-2-associated X levels were determined. Levels of DNA damage were measured as DNA single-strand breaks (SSBs) by the alkaline single-cell gel electrophoresis (comet) assay or as DNA adducts by (32)P-postlabelling analysis. B[a]P-induced up-regulation of CYP1A1 was >100-fold in S-phase-concentrated cells, but in G(0)/G(1)-phase- or G(2)/M-phase-concentrated cultures up-regulation occurred to a significantly lower extent. Consistent with this, B[a]P-treated S-phase-concentrated cultures exhibited markedly up-regulated P21(WAF1/CIP1), higher levels of dose-related increases in DNA SSBs, and increased DNA adduct levels presumably as a result of CYP1A1-mediated activation of B[a]P to B[a]P-diol-epoxide compared with the cultures enriched for the other cell cycle phases. Growth kinetics in vitro may be an important predeterminant of susceptibility to an exogenous pro-carcinogen in short-term test systems and these findings have important implications when extrapolating such results to a particular target-cell population in vivo.
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PMID:Growth kinetics in MCF-7 cells modulate benzo[a]pyrene-induced CYP1A1 up-regulation. 1723 83

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) and oxidized LDL (Ox-LDL), which accelerate the pathogenesis of arteriosclerosis, are thought to be involved in parthenogenesis caused by smooth muscle cell proliferation. In this study, we investigated the suppression mechanism of polycyclic aromatic hydrocarbons (PAHs) on the growth of an MDA-LDL-induced human acute monocyte leukemia suspension cell line (THP-1 cells). We found that PAHs suppressed MDA-LDL-induced THP-1 cell growth. Cotreatment with benzo[a]pyrene (BaP) or 3-methylchoranthrene (3-MC) decreased MDA-LDL-induced THP-1 cell growth, whereas treatment with benzo[e]pyrene (BeP) or pyrene, which is not a ligand for the arylhydrocarbon receptor (AhR), did not decrease THP-1 cell growth. Our findings clearly demonstrated that THP-1 cell growth, which was suppressed by PAHs, was restored by the addition of alpha-naphtoflavone, which is a partial antagonist to AhR. Moreover, it was shown that cotreatment with MDA-LDL and BaP markedly induced the expression of human cytochrome P4501A1 (hCYP1A1) messenger ribonucleic acid (mRNA) and significantly induced the expressions of p53 and p21 mRNAs. In support of these findings, AhR small interfering RNA suppressed the induced level of p21 mRNA and by BaP and the overexpression of hCYP1A1 significantly induced levels of p21 mRNA. On the other hand, the uptake rate of [(14)C]BaP into cells was increased more significantly by cotreatment with MDA-LDL than by treatment with [(14)C]BaP alone. These results strongly suggest that the suppression of MDA-LDL-induced THP-1 cell growth is caused by the increased uptake of PAHs, which strongly activate the AhR signal pathway accompanying DNA damage.
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PMID:Malondialdehyde-modified low density lipoprotein (MDA-LDL)-induced cell growth was suppressed by polycyclic aromatic hydrocarbons (PAHs). 2037 65

Organophosphorus pesticide (OPP) toxicity is believed to be mediated through inhibition of acetylcholinesterase (AChE). Given their widespread distribution in aquatic systems and their ability to undergo chemical transformation, their environmental impacts at sublethal concentrations in nontarget organisms have become an important question. We conducted a number of mammalian-cell genotoxic and gene expression assays and examined cellular biochemical changes that followed low-dose exposure of MCF-7 cells to fenitrothion, diazinon, and the aqueous degradate of diazinon, 2-isopropyl-6-methyl-4-pyrimidinol (IMP). After exposure to the OPPs at low concentrations (10(-12) M to 10(-8) M), greater than twofold elevations in micronucleus formation were noted in MCF-7 cell cultures that went on to exhibit greater than 75% clonogenic survival; these levels of chromosomal damage were comparable to those induced by 10(-6) M benzo[a]pyrene, a known genotoxic agent. At this low concentration range, a fenitrothion-induced twofold elevation in B-cell leukemia/lymphoma-2 (BCL-2) and cytochrome P450 isoenzyme (CYP1A1) gene expressions was observed. Principal component analysis-linear discriminant analysis (PCA-LDA) of derived infrared (IR) spectra of vehicle control (nonexposed) and OPP-exposed cells highlighted that both fenitrothion and diazinon induced marked biochemical alterations in the lipid, protein, and DNA/RNA absorbance regions. Our findings demonstrate that the two OPP parent chemicals and IMP degradate can mediate a number of toxic effects or cellular alterations at very low concentrations. These are independent of just selective inhibition of AChE, with potential consequences for nontarget organisms exposed at environmentally relevant concentrations. Further assays on relevant aquatic organism cell lines are now recommended to understand the mechanistic low-dose toxicity of these chemicals present in aquatic systems.
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PMID:Sublethal genotoxicity and cell alterations by organophosphorus pesticides in MCF-7 cells: implications for environmentally relevant concentrations. 2129 9

This review is focused on current information of avoidable environmental pollution and occupational exposure as causes of cancer. Approximately 2% to 8% of all cancers are thought to be due to occupation. In addition, occupational and environmental cancers have their own characteristics, e.g., specific chemicals and cancers, multiple factors, multiple causation and interaction, or latency period. Concerning carcinogens, asbestos/silica/wood dust, soot/polycyclic aromatic hydrocarbons [benzo(a) pyrene], heavy metals (arsenic, chromium, nickel), aromatic amines (4-aminobiphenyl, benzidine), organic solvents (benzene or vinyl chloride), radiation/radon, or indoor pollutants (formaldehyde, tobacco smoking) are mentioned with their specific cancers, e.g., lung, skin, and bladder cancers, mesothelioma or leukemia, and exposure routes, rubber or pigment manufacturing, textile, painting, insulation, mining, and so on. In addition, nanoparticles, electromagnetic waves, and climate changes are suspected as future carcinogenic sources. Moreover, the aspects of environmental and occupational cancers are quite different between developing and developed countries. The recent follow-up of occupational cancers in Nordic countries shows a good example for developed countries. On the other hand, newly industrializing countries face an increased burden of occupational and environmental cancers. Developing countries are particularly suffering from preventable cancers in mining, agriculture, or industries without proper implication of safety regulations. Therefore, industrialized countries are expected to educate and provide support for developing countries. In addition, citizens can encounter new environmental and occupational carcinogen nominators such as nanomaterials, electromagnetic wave, and climate exchanges. As their carcinogenicity or involvement in carcinogenesis is not clearly unknown, proper consideration for them should be taken into account. For these purposes, new technologies with a balance of environment and gene are required. Currently, various approaches with advanced technologies--genomics, exposomics, etc.--have accelerated development of new biomarkers for biological monitoring of occupational and environmental carcinogens. These advanced approaches are promising to improve quality of life and to prevent occupational and environmental cancers.
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PMID:A current global view of environmental and occupational cancers. 2192 81

We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration.
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PMID:Activation of aryl hydrocarbon receptor by benzo[a]pyrene increases interleukin 33 expression and eosinophil infiltration in a mouse model of allergic airway inflammation. 3255 21


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