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 471,332 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of green tea polyphenol fraction (GTP) on azoxymethane(AOM)-induced colon carcinogenesis was investigated in male Fischer rats. The rats were given AOM (7.4 mg/kg body weight) s.c. once a week for 10 weeks. A week after the treatment, they were divided into three groups: AOM-control (26 rats), AOM-GTP1 (26 rats) and AOM-GTP2 (25 rats). AOM-GTP1 and AOM-GTP2 groups respectively received 0.01 and 0.1% GTP in drinking water from week 11 to 26. AOM-control group received tap water throughout this experiment. Autopsy on week 26 showed that tumor incidence and average numbers of tumors per rat in the AOM-GTP1 and AOM-GTP2 groups were significantly lower than those of the AOM-control group: 38.1% and 47.6% versus 77.3%; 0.6 and 0.7 versus 1.5. Thus, it was concluded that GTP inhibited the development of AOM-induced colon carcinogenesis. The inhibition by GTP did not show significant dose dependence.
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PMID:Inhibition of azoxymethane-induced colon carcinogenesis in rat by green tea polyphenol fraction. 177 55

DNA aneuploidy and proliferative abnormalities were studied by flow cytometry in 169 colorectal specimens from 162 patients. Of 37 adenomas, three showed aneuploidy and another seventeen revealed a "near diploid" DNA pattern. The rate of aneuploid and "near diploid" DNA changes in 92 carcinomas was 53.3% and 23.9%, respectively. No correlation was seen between the ploidy distribution and the stage or histologic grade of the carcinomas. The S-phase fractions of both adenomas and carcinomas significantly increased from the diploid (8.1 +/- 0.8% and 7.8 +/- 0.9% respectively; mean +/- SEM) to the "near diploid" (14.9 +/- 1.2% and 12.6 +/- 1.5%) and aneuploid (20.4 +/- 1.3% and 11.4 +/- 1.6%) lesions. To better understand neoplastic progression at very early stages, flow cytometry was also performed on 195 colonic specimens of 44 rats treated by weekly subcutaneous injections of 21 mg/kg Dimethylhydrazine. There was a single "near diploid" carcinoma in this group, and all other induced neoplasms (39 carcinomas and 27 adenomas) revealed a diploid DNA pattern. The S-phase fractions were as follows: controls (38 untreated animals) 8.6 +/- 0.1%, normal mucosa (of Dimethylhydrazine exposed rats) 10.1 +/- 0.25% (p less than 0.0001), adenomas 13.9 +/- 0.6% (p less than 0.01), and carcinomas 14.7 +/- 0.6% (p less than 0.01). These findings support the conclusion that genomic alterations and proliferative abnormalities may already be present in premalignant human colonic lesions. However, despite strong morphological similarities, major biological differences exist between the Dimethylhydrazine-induced murine intestinal carcinogenesis and spontaneously occurring human colorectal neoplasms.
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PMID:DNA aneuploidy and proliferation in spontaneous human and dimethylhydrazine-induced murine colorectal carcinogenesis. 178 Nov 91

The only available marker of DNA adducts formed from 1-nitropyrene (1-NP) and DNA, N-(deoxyguanosin-8-yl)-1-aminopyrene, is derived from the nitroreduction pathway. Our studies, as well as those of others, have indicated that multiple DNA adducts are formed from 1-NP in vivo and in vitro. Thus the need for additional DNA adduct markers was apparent. Therefore, it was our goal to characterize the DNA adducts formed from 4,5-epoxy-4,5-dihydro-1-nitropyrene, a metabolite of 1-NP. The epoxide was incubated with calf thymus DNA (pH 5.4). The DNA was enzymatically hydrolyzed to deoxyribonucleosides which were analyzed by reverse phase HPLC. Three major peaks were obtained in yields less than 5%. The structural assignment of these adducts was made by comparison of their proton nuclear magnetic resonance spectra with those of cis- and trans-4,5-dihydro-4.5-dihydroxy-1-nitropyrene, and by long range coupling constants, decoupling experiments, D2O exchange, partitions and acid hydrolysis. Two adducts result from trans and one from cis addition of the N2-exocyclic amino group of deoxyguanosine to the C5-benzylic carbon of the epoxide ring. This is the first report that describes the structure of the DNA adducts formed with a ring-oxidized metabolite of 1-NP. On the basis of this finding we suggest that K-region oxides of 1-NP may be responsible for the formation of the putative 1-NP-DNA adducts in vivo.
Carcinogenesis 1991 Apr
PMID:Structural characterization of the major adducts formed by reaction of 4,5-epoxy-4,5-dihydro-1-nitropyrene with DNA. 184 68

Incident cases of large bowel cancer from the Swiss canton of Vaud over the period 1974-88 were analyzed in relation to the distribution of site by sex, age, marital status and detailed subsite. A total of 1,968 cases were registered in males and 1,958 in females, corresponding to overall age-standardized (world) rates of 32.2/100,000 males and 22.4/100,000 females. The frequency of ascending and transverse colon cancer was lower in males (18.2% and 9.3%) than in females (23.1% and 10.0%, respectively), but cancers of the sigmoid colon and rectum were proportionally more frequent in males (34.0 and 30.0% versus 29.9 and 24.6% in females). Anal cancer accounted for 4.0% of large bowel cancers in females, but only 1.2% in males. Analysis of age-specific rates showed comparable values for ascending colon cancer in both sexes and in relation to each subsequent age group, as well as in sigmoid and rectal cancers up to middle age, while a male excess for the latter cancers became evident after age 55. A female excess for anal cancer was apparent in any subsequent age group. Information on marital status was available on 2,398 decreased subjects. Never married cases accounted for 12.2% of women and 8.1% of males. The excess of unmarried women was somewhat larger in the colon than in the sigma and rectum groups, but there was no evidence of excess of never married females for anal cancer. These data confirm that there are appreciable intersex heterogeneities in the descriptive epidemiology of various subsites of large bowel cancer, as well as complex interactions between sex and age, which may be related to female hormone correlates of intestinal carcinogenesis. Whatever the main biological mechanism(s), these data show noticeable similarities for both sexes in the descriptive epidemiology of cancers arising in the left colon and rectum, but noticeable differences with the right colon. Even more substantial are the differences with anal cancer, which should be linked to its venereal correlates.
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PMID:Patterns of large bowel cancer by subsite, age, sex and marital status. 186 55

The relationship between use of oral contraceptives (OCs) and other contraceptive methods and the risk of ovarian cancer was examined in a combined analysis of 3 hospital-based case-control studies conducted in Italy, the United Kingdom, and Greece, for a total of 971 ovarian cancer cases and 2,258 controls under age 65. Compared with never-users, the combined multivariate relative risk (RR) for ever-users was 0.6 (95% confidence interval, CI = 0.4-0.8) and the estimates were consistent in the 3 datasets. The protection was also similar across strata of age and parity. Considering various measures of OC use, available in the Italian and British datasets only, the protection conveyed on ovarian cancer risk increased with the duration of use and persisted in the medium-long period: the RR in women reporting their last OC use greater than or equal to 15 years prior to diagnosis was 0.5 (95% CI = 0.2-1.0). The risks in ever-users were appreciably lower in those women who reported their first OC use before 25 years of age (RR = 0.3 for first use before age 25, 0.8 for first use at age 25-34 and 0.7 at 35 years or after). Such findings emerged similarly from Italian and British data. This combined analysis, besides offering further quantitative estimates of the protective effects of OCs on ovarian cancer risk in European populations, provides useful insights into the time pattern of the relationship between OC use and ovarian carcinogenesis, suggesting that the protection persists for 15 years or more after cessation of use and may be larger for use at younger age.
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PMID:Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use. 187 72

The proinflammatory effects of passive inhalation of cigarette smoke were investigated by exposing a total of 16 healthy, young nonsmokers (mean age 29 +/- 1.4 yr, 11 women and five men) to actively smoking individuals in a poorly-ventilated room. Neutrophil functions were measured before and after 3 h of exposure to cigarette smoke. Passive cigarette smoking was associated with increased leukocyte counts (mean increase 33%, p less than 0.005), chemotaxis (57%, p less than 0.001), and release of reactive oxidants (71%, p less than 0.005) by stimulated neutrophils. These results were confirmed in a second study designed to eliminate the possible complicating effects of serial venepuncture. Plasma concentrations of the proinflammatory cytokines interleukin-1 (IL-1) alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) were not affected by passive smoking. These results indicate that inhalation of sidestream tobacco smoke promotes systemic priming of neutrophils. These potentially proinflammatory events may induce oxidant-mediated tissue damage and carcinogenesis in the lungs of passive smokers.
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PMID:Passive smoking by humans sensitizes circulating neutrophils. 189 96

Nitrated polycyclic aromatic hydrocarbons are environmental pollutants that have been shown to arise from a variety of sources, including diesel exhaust emissions and urban air. Most of these compounds are mutagenic in in vitro tests, and several have been shown to be carcinogenic in animals. We have investigated the kinetics of the metabolism of two of these compounds, 1-nitropyrene and 3-nitrofluoranthene, using rabbit liver aldehyde oxidase, an enzyme that has been shown to catalyze the bioactivation of 1-nitropyrene. The nitro-reduction of 20 microM [4,5,9,10-3H]1-nitropyrene or 20 microM [4-3H]3-nitrofluoranthene by aldehyde oxidase required the presence of flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD), and was inhibited by oxygen in a concentration-dependent manner. In contrast, the aldehyde oxidase oxidation of the electron donor 1-methylnicotinamide did not require FMN or FAD, indicating that the aldehyde oxidase was not isolated as an apoenzyme. The aldehyde oxidase Km and Vmax for 1-nitropyrene were 4.2 microM and 16.3 pmol/min/unit enzyme, while the respective values for 3-nitrofluoranthene nitroreduction were 1.9 microM and 5.4 pmol/min/unit enzyme. The requirement for flavins in the nitroreduction of 1-nitropyrene and 3-nitrofluoranthene suggests that reduced free flavins may be required in cytosolic nitroreduction of 1-nitropyrene and 3-nitrofluoranthene. More importantly, the inhibition of nitroreduction by concentrations of oxygen that are representative of intracellular concentrations strongly suggests that the reasons for the apparent lack of 1-nitropyrene nitroreduction in vivo may be due to oxygen-mediated oxidation of a reduced metabolite of 1-nitropyrene.
Carcinogenesis 1991 Sep
PMID:Kinetics and cofactor requirements for the nitroreductive metabolism of 1-nitropyrene and 3-nitrofluoranthene by rabbit liver aldehyde oxidase. 189 13

Cultured murine keratinocytes respond to specific Ca2+ levels in medium (Ca0) by expressing markers of terminal differentiation. A Ca0 of 0.05 mM selects for a basal cell phenotype, whereas spinous cell characteristics occur in 0.12 mM Ca2+ and cornified envelopes develop in 1.0 mM Ca2+. An increase in inositol phosphate (InsP) metabolism is associated with higher Ca2+ in the medium. The magnitude of Ca(2+)-stimulated InsP turnover is Ca0-dependent, whereas Ca0 of 0.05, 0.12 or 1.4 mM resulted in a graded, sustained (greater than 24 h) increase in InsPs. Diacylglycerol (DAG) levels similarly increased in a graded manner. The major inositol trisphosphate (InsP3) to accumulate was Ins-1,3,4-P3 while Ins-1,4,5-P3 increased transiently. Neoplastic keratinocyte cell lines, 308 and SP-1, which produce benign tumors and have a mutated c-rasHa gene, do not express markers of differentiation in response to Ca2+. Basal InsP and DAG are 2- and 5-fold higher respectively in the neoplastic cells relative to normal keratinocytes. However, the metabolic profiles of InsPs were similar in normal and neoplastic cells. In neoplastic cells, InsP metabolism was stimulated even further following a Ca2+ increase, and this was graded to the Ca0. The unusual, sustained Ca(2+)-graded InsP response in normal cells is consistent with the turnover of InsP contributing to the signals controlling expression of markers of differentiation. Very high InsP turnover and DAG levels, as in neoplastic cells, may be inhibitory to marker expression.
Carcinogenesis 1991 Sep
PMID:Changes in inositol phosphate metabolism are associated with terminal differentiation and neoplasia in mouse keratinocytes. 189 24

Bay region diolepoxides of polynuclear aromatic hydrocarbons (PAHs) generally are more tumorigenic than their parent PAHs in newborn mice. This contrasts to the results obtained in mouse skin, in which the same diolepoxides are frequently less tumorigenic than their parents. In order to evaluate mechanism(s) responsible for this behavior we have investigated the binding of metabolites of [3H]benzo[a]pyrene (B[a]), [3H]5- and [3H6]6-methyl-chrysene (5-MeC and 6-MeC) and their corresponding dihydrodiols and bay region diolepoxides to pulmonary and hepatic DNA in male and female newborn mice and compared the results with their tumorigenic activities. Groups of 1 day old mice were treated with 0.4 or 4 nmol of the appropriate compounds in DMSO by i.p. injection. HPLC analysis of DNA hydrolysates obtained 24 h after treatment indicated that levels of diolepoxide-DNA adducts following treatment with (+-)-[3H]7,8-dihydroxy-7,8-dihydroB[a]P and (+-)-[3H]anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydroB[a] P are 5- and 10-fold higher than those formed from [3H]B[a]P. The major products (70-80%) released upon enzymatic hydrolysis of DNA following treatment with [3H]B[a]P, [3H]5-MeC and [3H]6-MeC were unidentified polar compounds. Levels of these unknown products were lower and formation of diolepoxide--DNA adducts higher when test compounds were changed from parent PAHs to the corresponding dihydrodiols and diolepoxides. Comparison of these results with those of tumorigenesis studies indicates a correlation between formation of B[a]P-diolepoxide--DNA adducts and induction of tumors in newborn mouse lung, but not in liver. These observations are consistent with the high sensitivity of the newborn mouse lung towards the tumorigenic effects of bay region diolepoxides. Previous studies have demonstrated that 1R,2S-dihydroxy-3S,4R,epoxy, 1,2,3,4-tetrahydro-5-MeC (5-MeC-1R,2S-diol-3S,4R-epoxide) is a potent lung tumorigen while the corresponding diol-epoxide of 6-MeC had no effect in newborn mice. From the results of the present study, we estimate that at equimolar doses the formation of diolepoxide--DNA adducts from 5-MeC-1R,2S-diol-3S,4R-epoxide would be at least 20-fold greater than from the corresponding diolepoxide of 6-MeC in newborn mouse lung. Thus, the higher tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide compared to that of the corresponding diol epoxide of 6-MeC is partially due to its greater extent of DNA damage.
Carcinogenesis 1991 Sep
PMID:Comparative DNA binding of polynuclear aromatic hydrocarbons and their dihydrodiol and bay region diolepoxide metabolites in newborn mouse lung and liver. 189 26

Treatment of DNA digests with nuclease P1 prior to 32P-labeling of adducts has previously been shown to enhance the sensitivity of the 32P-postlabeling assay for the detection of aromatic carcinogen-DNA adducts. The enhancement was based on the ability of nuclease P1 to remove the 3'-phosphate from normal nucleotides but not the corresponding phosphate from most aromatic adducted nucleotides. We investigated the utility of another 3'-dephosphorylating enzyme, nuclease S1, for this purpose, and found it to be as effective as nuclease P1. The recovery of DNA adducts derived from benzo[a]-pyrene (B[a]P), benzoquinone (BQ) and 2-acetylaminofluorene (AAF) was comparable after enhancement with either enzyme. Some differences were, however, observed. Recovery of a minor B[a]P adduct was 1.5 times higher by the S1 procedure. Among minor adducts of BQ, two showed higher values (2.8- and 6.1-fold) by the S1 procedure and one by the P1 procedure (2.4-fold). The major AAF adduct, deoxyguanosine-C8-AF, exhibited poorer recovery (1-11%) by either procedure, while the minor adducts, deoxyguanosine-N2-AAF and deoxyguanosine-C8-AAF, showed better recovery (2-3 times) than by the enhancement procedure involving extraction of adducts into butanol. Our results show that the nuclease S1 assay can complement the nuclease P1 assay, with improved recoveries for some adducts. Considering the complexity of the postlabeling assay, this additional variant may prove useful in unequivocal detection of DNA adducts.
Carcinogenesis 1991 Sep
PMID:Nuclease S1-mediated enhancement of the 32P-postlabeling assay for aromatic carcinogen-DNA adducts. 189 35


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