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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of lung adenomas in strain A mice following multiple injections of 17 alkyl halides and of 3 base analogs was investigated. A slight but significant increase in the average number of lung tumors per mouse was noted following the administration of methyl iodide, n- and i-propyl iodide, sec- and tert-butyl chloride, i-, sec-, and tert-butyl bromide, and n- and sec-butyl iodide. The administration of comparable doses of ethyl bromide, ethyl iodide, n-butyl chloride, benzyl chloride, and 1-chloromethylnaphthalene to mice resulted in no significant increase in the frequency of lung tumors over that seen in vehicle-treated control mice. n-Butyl bromide and tert-butyl iodide similarly appeared to have no significant effect on the lung tumor frequency, but these compounds were too toxic to be tested at the high dosages used with the other alkyl halides. 5-Iodo-, 5-bromo-, and 5-fluorodeoxyuridine also appeared to have no significant effect on the lung tumor frequency. These results indicate that a high proportion of low-molecular-weight alkyl halides may be weakly carcinogenic and provide evidence supporting an electrophilic hypothesis of carcinogenesis.
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PMID:Bioassay of alkyl halides and nucleotide base analogs by pulmonary tumor response in strain A mice. 12 6

The flame retardants tris(2,3-dibromopropyl)phosphate, tetrakis(hydroxymethyl)phosphonium chloride, and polyvinyl bromide were tested for carcinogenic activity by skin application 3 times weekly in random-bred female ICR/Ha Swiss mice for 420 to 496 days. Tris(2,3-dibromopropyl)phosphate at two dose levels (30 mg and 10 mg/application) induced benign and malignant tumors of the skin, forestomach, and oral cavity (tongue and gingiva) in a statistically significant number of mice (30/group). A statistically significant incidence of papillary tumors of the lung was observed at both dosages, and the higher dose also resulted in one mouse with a tubular adenoma of the kidney. Tetrakis(hydroxymethyl)phosphonium chloride (2 mg/application, 60 mice) and polyvinyl bromide (0.1 ml latex suspension/application, 30 mice) were inactive. Polyvinyl bromide was also injected s.c. into another group of female ICR/Ha Swiss mice once weekly for 48 weeks, and the mice were observed for a total of 60 weeks. Liposarcomas were induced in 19 of 30 mice, which was ascribed to physical carcinogenesis. Appropriate solvent and no-treatment control groups were included.
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PMID:Mouse skin carcinogenicity tests of the flame retardants tris(2,3-dibromopropyl)phosphate, tetrakis(hydroxymethyl)phosphonium chloride, and polyvinyl bromide. 68 15

The essential role of Rauscher leukemia virus (RLV) multiplication in viral-chemical co-carcinogenesis was investigated by the use of ethidium bromide (EtBr) as an inhibitor of viral complementary DNA (cDNA) integration in the host genome. EtBr inhibited co-carcinogenic transformation when present at the time of RLV inoculation but was ineffective when added to preinfected cells. Inhibitors of protein synthesis, puromycin and cyclohexamide also inhibited co-carcinogenic transformation of chronically infected cells. Purified rat interferon used at a concentration which inhibited 85% of RLV production did not modify the course of co-carcinogenic transformation. The implications of these observations in terms of the possible role of the virus-specific protein (s) in the co-carcinogenic process are discussed.
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PMID:Chemical-viral co-carcinogenesis: requirement for leukemia virus expression in accelerated transformation. 99 12

8-Bromo-cAMP and substances elevating cAMP levels within cells, such as forskolin, cholera toxin, and Bordetella pertussis-invasive adenylate cyclase (BPAC), suppress the growth of cultured granulosa cells cotransfected by simian virus-40 (SV40) DNA and Ha-ras oncogene concomitantly with the induction of steroidogenesis and without affecting oncogene expression. We, therefore, tested the hypothesis that cAMP can modulate tumorigenesis and metastatic spread of these cells in vivo. The cotransfected cells induced rapid development of tumors when injected sc in nude mice. Tumor development was faster in less differentiated cotransfected cells originating from preantral ovarian follicles than in those obtained from highly differentiated transformed cells originating from preovulatory follicles. Cells transfected by SV40 DNA alone produced only slow-growing small tumors. Metastatic lesions of cotransfected cells were most abundant in lung and less frequent in ovaries, kidney, and spleen. No metastatic lesions were found in the liver. However, metastatic spread was dramatically suppressed when cotransfected cells injected into nude mice were pretreated with the invasive BPAC. In contrast, no suppression of metastases was observed when the cells were pretreated with 8-bromo-cAMP, forskolin, or cholera toxin. Removal of forskolin in cultured cotransfected cells yielded a rapid decrease in cAMP levels. In contrast, high levels of cAMP persist in cell cultures even several hours after 1-h pretreatment and subsequent removal of BPAC from the medium of culture cotransfected cells. It is suggested that the inhibitory effect of BPAC on the metastatic spread of these cells is due to prolonged elevation of cAMP in vivo. The newly established granulosa cell lines transformed by SV40 and the Ha-ras oncogene can serve as a model for further studies of cAMP modulation of carcinogenesis in ovarian malignancies.
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PMID:Adenosine 3',5'-monophosphate suppresses metastatic spread in nude mice of steroidogenic rat granulosa cells transformed by simian virus-40 and Ha-ras oncogene. 131 28

Fifteen specific inhibitors of DNA topoisomerases I and II were used to elucidate whether these enzymes participate in the excision repair of UV-induced DNA damage, monitoring DNA repair synthesis in confluent saponin-permeabilized human fibroblasts. To achieve a sufficient degree of accuracy dose--response experiments were performed, analysed by linear regression, and the concentrations at which repair activity was reduced to 50% were calculated and designated K50. Camptothecin, a specific inhibitor of topoisomerase I did not markedly diminish DNA repair synthesis. Similarly, when combined with topoisomerase II inhibitors [nalidixic acid, oxolinic acid, 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside) (etoposide), 4'-demethylepipodophyllotoxin-thenylidene-beta-D-glucoside (teniposide), 1,4-dihydroxy-5,8-bis ((2-[(2-hydroxyethyl)amino]ethyl)amino)-9,10-anthracenedione (mitoxantrone), 5-(N-phenyl-carboxamido)-2-thiobarbituric acid (merbarone) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)], it did not lower K50 values determined for topoisomerase II-specific drugs in separate experiments. The effects observed can be classified according to the mechanism of action the inhibitors exhibit. (i) Novobiocin and coumermycin, inhibitors of the ATPase subunit of topoisomerase II, completely reduced DNA repair synthesis. (ii) Inhibition of repair was also found for ethidium bromide, quinacrine and distamycin, drugs known to modify the DNA substrate by intercalation or binding to the DNA minor groove. (iii) Inhibitors acting through intercalation and, simultaneously, binding to the cleavable DNA-topoisomerase complex (m-AMSA, mitoxantrone, doxorubicin and daunorubicin) also suppressed reparative DNA synthesis. (iv) Only small effects were observed for etoposide, nalidixic acid and oxolinic acid, whereas teniposide caused marked inhibition of DNA repair synthesis. (v) Merbarone, a novel type of topoisomerase II inhibitor, blocked UV-induced DNA repair drastically. The results are best explained by assuming that in UV-irradiated human fibroblasts the 180 kDa form of topoisomerase II is the main target enzyme for inhibitors which suppressed DNA excision repair and that this isozyme is involved in steps preceding repair-specific DNA incision.
Carcinogenesis 1992 Dec
PMID:The function of DNA topoisomerases in UV-induced DNA excision repair: studies with specific inhibitors in permeabilized human fibroblasts. 133 77

Promotion of 'initiated' JB6 epidermal cells to the tumor phenotype can be effected by 12-O-tetradecanoylphorbol-13-acetate treatment, by stimulation of epidermal growth factor (EGF) receptor activity with EGF or transforming growth factor alpha and by exposure to the isoquinoline derivative H7. When these cells were incubated with pertussis toxin (PTX), induction of anchorage-independent growth by all four promoting substances was suppressed. The inhibition is specific since cell proliferation is not affected, suggesting that activation of a Gi protein is essential for promotion of the epidermal cells. This interpretation is strongly supported by the observation that the wasp poison mastoparan, which is known to mimic receptor-mediated activation of certain Gi proteins, also promoted anchorage independence. Immunological data and partial amino acid sequence analysis of ADP-ribosyl alpha i isolated from PTX-treated JB6 cells indicate that a Gi-2 protein is a mediator to tumor promotion in this system. The inhibitory action of 4-bromophenacyl bromide may point to a coupling of the Gi protein to phospholipase A2. From our data we infer that promoters induce the tumor phenotype in 'initiated' JB6 epidermal cells by activating epigenetically the same Gi protein that in a number of adrenal and ovarian tumors appears to be persistently activated by mutational events.
Carcinogenesis 1992 Dec
PMID:Epigenetic activation of Gi-2 protein, the product of a putative protooncogene, mediates tumor promotion in vitro. 147 50

A polymerase chain reaction-based procedure was used for the detection of DNA length polymorphisms generated by naturally occurring genetic deletions or insertions of known sequence. This method consists of a simple one-step assay that does not require any restriction enzyme analysis or Southern blot hybridization, allowing identification in ethidium bromide-stained gels. The procedure described here was used to detect loss of heterozygosity at various loci, including the Hbb beta-globin gene cluster, in chemically induced mouse skin tumors, using a variety of tissue preparations, including microdissection of formalin-fixed, paraffin-embedded specimens, short-term cultures, and fluorescence-activated cell sorting of epithelial populations. This approach may be useful in detecting tumor-specific reduction to homozygosity at polymorphic chromosomal loci, allowing the mapping of putative tumor-suppressor loci involved in carcinogenesis.
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PMID:Detection of loss of heterozygosity in formalin-fixed paraffin-embedded tumor specimens by the polymerase chain reaction. 199 58

In order to study the mechanism of cancer production by aflatoxin B1 (AFB1) in extrahepatic tissues which have relatively low cytochrome P450 monooxygenase (P450) activity, we have examined prostaglandin H synthase (PHS)-mediated AFB1 activation [( 3H]AFB1-DNA binding). [3H]AFB1 was activated by both purified PHS and microsomal PHS from guinea-pig kidney and liver, as well as by P450 in lung, kidney and liver microsomes, though P450-mediated [3H]AFB1-DNA binding in lung and liver was much higher than that catalyzed by PHS. Arachidonic acid (AA)-dependent [3H]AFB1-DNA binding could be inhibited by the PHS inhibitor indomethacin (0.1 mM), but was enhanced by the P450 inhibitor SKF-525A (3 mM), confirming that the reaction was independent of P450. Pulmonary PHS-mediated [3H]AFB1--DNA binding was less than 0.1 pmol [3H]AFB1/mg protein/min. HPLC analysis showed only minimal formation of [3H]AFM1 and [3H]AFQ1 by PHS, confirming that the low rate of PHS-dependent [3H]AFB1-DNA adduct formation was not due to conversion of AFB1 to other metabolites by PHS. The omission of AA did not diminish [3H]AFB1-DNA binding. In AA-free incubates, indomethacin inhibited, and SKF-525A enhanced, [3H]AFB1-DNA binding to a similar degree as in complete incubates, indicating that DNA binding in AA-free incubates was catalyzed by PHS. This reaction was also inhibited by 4-bromophenacyl bromide, a phospholipase A2 inhibitor, by 92%. These data are consistent with previous reports indicating the ability of AFB1 to stimulate the release of endogenous AA from membranes, presumably by stimulating phospholipase A2 activity, which may lead to enhanced bioactivation of AFB1 by PHS in vivo.
Carcinogenesis 1990 Nov
PMID:In vitro prostaglandin H synthase- and monooxygenase-mediated binding of aflatoxin B1 to DNA in guinea-pig tissue microsomes. 212 80

The generation of superoxide and related free radicals and the mobilization of catalytic iron due to ethanol metabolism have been suggested as mechanisms of alcohol-induced liver injury as well as of the increased risk of cancer observed in alcoholics. Cleavage of double stranded DNA is produced by both free radicals as well as by catalytic iron. The effects of ethanol metabolism on DNA cleavage were therefore studied in vitro as well as in vivo in isolated hepatocytes. Intactness of double stranded DNA was studied by measuring ethidium bromide fluorescence after DNA electrophoresis. In vitro, the metabolism of acetaldehyde by aldehyde oxidase caused cleavage of Lambda phage DNA. Cleavage was inhibited by both superoxide dismutase and desferrioxamine indicating the role of superoxide radicals and catalytic iron respectively. Studies with HIND III digests of the Lambda phage indicate a lack of specificity in the breaks with respect to nucleotide sequences. Addition of EDTA greatly enhanced cleavage. In vivo, ethanol metabolism caused minimal breakage in hepatocyte DNA and addition of acetaldehyde (100 microM) markedly enhanced cleavage; all cleavage was inhibited by desferrioxamine. The metabolism of ethanol to acetaldehyde and the further metabolism of acetaldehyde by aldehyde oxidase generates free radicals and mobilizes iron; these may contribute to alcohol-induced injury and carcinogenesis.
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PMID:DNA cleavage during ethanol metabolism: role of superoxide radicals and catalytic iron. 217 Jul 94

A sensitive assay for quantitative determination of the vinyl chloride (VC)-induced cyclic DNA adduct N2,3-ethenoguanine (EG) was developed. The method is based on the detection of EG as its di-pentafluorobenzyl derivative (3,5-PFB2-EG). This compound exhibited good gas chromatographic properties and was detected with high sensitivity by gas chromatography with electron capture detection (limit of detection 300 amol/microliters injected solution) or with negative ion chemical ionization mass spectrometry monitoring the [M-181]-fragment ion at m/z 354 (GC-NICI-MS, limit of detection 190 amol/microliters injected solution). EG, its 13C-labeled analog [13C4]-EG and 3,5-PFB2-EG were synthesized and characterized by UV and fluorescence spectrophotometry, 1H- and 13C-NMR spectroscopy and mass spectrometry. The standards were used to optimize the isolation of EG and its derivatization with pentafluorobenzyl bromide (electrophore labeling) at fmol quantities. DNA solutions were spiked with EG, the DNA was depurinated by mild acid hydrolysis, and EG was isolated from the hydrolysates by low-pressure strong cation exchange chromatography with subsequent C18 solid-phase extraction. The extracted EG was electrophore labeled and 3,5-PFB2-EG was detected using GC-NICI-MS. [13C4]EG served as internal standard. 3,5-PFB2-EG was quantitated relative to its 13C-labeled analog by measuring the ion ratio m/z 354/358. The limit of detection for the complete method was 60 fmol EG/mumols guanine. The method was applied to liver DNA from young Sprague-Dawley rats exposed to 600 p.p.m. VC from day 10 through day 14 after birth. The EG concentration in these samples was 1.8 +/- 0.3 pmol/mumols guanine.
Carcinogenesis 1990 Aug
PMID:Vinyl chloride-induced DNA adducts. I: Quantitative determination of N2,3-ethenoguanine based on electrophore labeling. 238 13


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