Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: B0001 .4
 471,332 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The highly tumorigenic isomer (+)-7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE] and its non-tumorigenic enantiomer (-)-anti-BPDE are known to react predominantly with the exocyclic amino group (N2) of deoxyguanine in DNA and to form adducts of different conformations. The spectroscopic characteristics (UV absorbance, fluorescence and circular dichroism) of stereochemically defined (+)-trans, (-)-trans, (+)-cis and (-)-cis d(5'-CACATGBPDETACAC) adducts in the single-stranded form, or complexed with the complementary strand d(5'-GTGTACATGTG) in aqueous solution, were investigated. The spectroscopic characteristics of the double-stranded d(5'-CACATGBPDETACAC).d(5'-GTGTACATGTG) adducts can be interpreted in terms of two types of conformations. In site I-type conformations, there is an approximately 10 nm red shift in the absorption maxima, which is attributed to significant pyrenyl residue-base interactions; in site II-type adducts, the red shift is only approximately 2-3 nm, and the pyrene ring system is located at external, solvent-exposed binding sites. The spectroscopic characteristics of the BPDE-modified duplexes are of the site II type for the (+)- and (-)-trans, and of the site I type for the (+)- and (-)-cis adducts. In adducts derived from the binding of (+)-anti-BPDE to poly(dG-dC).(dG-dC) and poly(dG).(dC), the trans/cis BPDE-N2-dG adduct ratio is 6 +/- 1; in the case of (-)-anti-BPDE this ratio is only 0.4 +/- 0.1 and 0.6 +/- 0.15 in poly(dG-dC).(dG-dC) and poly(dG).(dC) respectively. The spectroscopic properties of these BPDE-modified polynucleotide adducts are consistent with those of the BPDE-modified oligonucleotide complexes; the cis adducts are correlated with site I adduct conformations, while the trans adducts are of the site II type. The correlations between adduct characteristics and biological activities of the two BPDE enantiomers are discussed.
Carcinogenesis 1991 Nov
PMID:Spectroscopic characteristics and site I/site II classification of cis and trans benzo[a]pyrene diolepoxide enantiomer-guanosine adducts in oligonucleotides and polynucleotides. 193 95

The potent food mutagen 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ) is carcinogenic in the CDF1 mouse, affecting the liver, lungs and forestomach. Females are approximately twice as sensitive as males to liver tumor induction. Using 32P-postlabeling assays, the dose-response of IQ-DNA adduct formation was determined in various organs of male and female CDF1 mice after single p.o. doses of IQ. To determine the possible correlation between IQ-DNA adduct formation, persistence and tumorigenicity in target organs, young adult male and female CDF1 mice were treated with a single p.o. dose (50 mg/kg) of IQ, and IQ-DNA adducts were isolated and quantitated in liver, lungs, forestomach, small intestine and large intestine over a 24 day period. In the range of 5-50 mg IQ/kg, IQ-DNA adduct formation was related to dose in all organs examined (liver, lungs, stomach, small intestine, large intestine). Total adduct formation (expressed as relative adduct labeling, RAL) 24 h after administration was highest in the liver (6.4-6.9 x 10(-7)) with lower levels, in decreasing order, in the large intestine, small intestine (non-target organs), forestomach and lungs (target organs). In all cases the major adduct, comprising 68-79% of the total, co-chromatographed with standard N-(deoxyguanosin-8-yl)-IQ. Up to three additional IQ-specific adducts could be detected. Except in the liver, adduct levels 24 h after administration of IQ were 2- to 3-fold higher in females than in males. There was no preferential retention of any one of the four adducts 1-24 days after administration of IQ. Beyond day 4 after administration, total adducts in the liver of females were approximately 2-fold higher than those in males, and the rate of removal from female lung was approximately 2-fold faster than that from male lung during the 1-24 day time period. Both these findings correspond to the known sex differences in IQ-induced tumor incidences in these organs. The higher adduct levels in non-target organs (intestines) as compared to target organs (lungs and stomach), combined with the absence of differential persistence of any individual adduct indicates that, in addition to adduct formation and persistence, other factors contribute to the target organ specificity of IQ in CDF1 mice.
Carcinogenesis 1991 Nov
PMID:Sex differences in the formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in CDF1 mice. 193 5

Development of secondary malignancies following treatment of Hodgkin's disease with radiation (central axis midline dose of 3600-4500 cGy) is a recognized risk, and the incidence in breast cancer has been reported to increase by a factor of 4.3 (95% confidence level 2.0 to 8.4) for patients treated with mantle irradiation. Increased incidence of breast cancer has also been shown in atomic bomb survivors, women who underwent multiple fluoroscopic examinations, and women treated for postpartum mastitis. The dose response, however, for radiation dose above 1000 cGy is virtually unknown. Quantitative analysis of carcinogenesis after radiation is exacerbated by the large dose gradient across the breast (300-4200 cGy for midline doses of 4000 cGy), large individual variation in breast size and treatment field position. We have developed differential dose volume histograms calculated using a 3-dimensional (Eg TAR) algorithm as a potential tool for retrospective and prospective epidemiological evaluation. The breast volume forms a bimodal distribution with respect to dose and with further analysis other quantities, such as mean dose and integral dose, can be calculated from the histograms. Using the mean dose, the linear model for carcinogenesis predicts an increased incidence of secondary breast cancer by a factor of 11.6 and 9.6 for the left and right breast, respectively. The dose calculations has been corrected for inhomonogenities 3-dimensionally and test of the accuracy has been included.
 ...
PMID:Dosimetry of the breast for determining carcinogenic risk in mantle irradiation. 193 34

The aim of this study has been to define cytotoxic mechanisms that may cause clonal expansion in the liver of pre-carcinogenic cells. An in vitro model, which has been described previously, was used. Hepatocytes were isolated from carcinogen-treated rats and a high proportion of the cells were gamma-glutamyltranspeptidase (GGT)-positive. The cells were incubated in suspension and exposed to toxic agents in concentrations that induced a moderate increase in cellular leakage within 3 h. Samples were withdrawn and sampled cells were then allowed to attach to collagen-coated plates. Attached cells were stained and the ratio of GGT-positive/GGT-negative cells (GGT-ratio) was determined. The initial GGT-ratio was 10.4 +/- 4.7% and an increased ratio was taken as a sign of toxicity that resulted in a selection of GGT-positive cells. In a first series of experiments it was shown that hydroquinone and menadione increase the GGT-ratio, while diquat, sodium selenite, diethyl maleate or phorone do not. However, diethyl maleate in combination with diquat increased the GGT-ratio. Hydrogen peroxide (5 mM) increased the GGT-ratio as effectively as hydroquinone (0.3 mM). Lower concentrations of H2O2 (0.05 mM) increased the GGT-ratio in GSH-depleted cells. The changes induced by hydroquinone and H2O2 in low concentration were reversible. In another series of experiments, plates coated with antibodies against beta 1-integrin were used. An increase in the GGT-ratio was obtained with anti beta 1-integrin, but not with broad spectrum anti-rat hepatocyte or anti-rat beta 2-microglobulin antibodies as substrata. These data suggested an involvement of the beta 1-integrin in the selection. Taken together, these data indicate that GGT-positive hepatocytes are protected against GSH depletion and oxidative stress that may result in reversible receptor alterations.
Carcinogenesis 1990 Jan
PMID:gamma-Glutamyltranspeptidase-positive rat hepatocytes are protected from GSH depletion, oxidative stress and reversible alterations of collagen receptors. 196 30

To characterize the potential role of high-l.e.t. radiation in respiratory carcinogenesis, the cytotoxic and transforming potency of 5.5 Me V alpha-particles from electroplated sources of 238Pu were determined using primary cultures of rat tracheal epithelial cells. The alpha-particle response was compared to the effects of 280 kVp X-rays and of the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. Increasing the alpha-particle dose caused an exponential decrease in survival with a D37 of 1.6 Gy. X-rays also caused a dose-dependent decrease in survival (D37 = 3.6 Gy) but the survival curve had a significant shoulder. The RBE for cell killing by alpha-particles versus X-rays varied with dose, and ranged between 4 and 1.5 for alpha doses in the range 0.2-4 Gy. At equally toxic doses (relative survival 0.18-0.2), all three agents induced similar frequencies of preneoplastic transformation. For preneoplastic transformation induced by doses of alpha- and X-radiations giving 80 per cent toxicity, an alpha RBE of 2.4 was derived. The similar RBEs for cell killing and for preneoplastic transformation suggest an association between the type or degree of radiation-induced damage responsible for both cell killing and cell transformation.
 ...
PMID:Alpha-particles induce preneoplastic transformation of rat tracheal epithelial cells in culture. 196 3

The relationship between selected urinary tract and genital diseases and the risk of bladder cancer was analyzed using data from a case-control study of 364 cases of bladder cancer and 447 controls hospitalized for acute, nonneoplastic, nongenital tract conditions, unrelated to known or suspected risk factors for bladder cancer. Cystitis was reported by 20% of the cases and 8% of the controls, corresponding to a multivariate relative risk (RR) of 3.8 (95% confidence interval, 2.4 to 5.9). No association was observed with urinary tract stones (RR = 1.2). With reference to genital diseases, the RR was elevated for gonorrhea (RR = 2.8, 95% confidence interval, 1.0 to 4.5) and condylomata acuminata (RR = 5.9, 95% confidence interval 1.0 to 3.6) but not for syphilis. The risk increased with the number of episodes of cystitis (RR = 5.0 for greater than or equal to 4 episodes, chi 2 for trend = 33.04, P less than 0.001), was higher during the last 15 years after the first episode (RR = 5.1 versus 2.3 for over 15 years), and was not heterogeneous across strata of age and sex. The interaction between urinary tract infections and tobacco appeared multiplicative, with RR = 2.4 for ever smoking, 3.2 for cystitis alone, and 10.3 for both exposures. The present study, besides providing further quantitative evidence of a relationship between urinary tract infections (and, possibly, some genital infections, too) and bladder cancer, indicates that the role of infections is probably in one of the latter (promoting) stages of the process of carcinogenesis and suggests a multiplicative interaction with smoking. In terms of prevention and public health, therefore, it is thus important to avoid at least one exposure for subjects with a history of urinary tract infections who smoke tobacco.
 ...
PMID:Genital and urinary tract diseases and bladder cancer. 198 79

The effect of the opioid receptor agonist methionine enkephalin (Met-enkephalin) and the opioid receptor antagonist naloxone on colonic carcinogenesis induced by azoxymethane was investigated in Wistar rats. Rats received ten weekly injections of 7.4 mg/kg of body weight of azoxymethane and injections of Met-enkephalin (50 micrograms/kg of body weight), naloxone (2 mg/kg of body weight), or Met-enkephalin (50 micrograms/kg of body weight) plus naloxone (2 mg/kg of body weight) once every 2 days. In wk 40, the group treated with Met-enkephalin had a significantly increased incidence of colonic tumors. A combination of Met-enkephalin and naloxone attenuated the enhancing effect by Met-enkephalin on the development of colonic tumors. Administration of naloxone alone had no influence on colonic tumorigenesis. During and after administration of the carcinogen, the bromodeoxyuridine-labeling indices of the colon mucosa and/or cancers were significantly increased in rats treated with Met-enkephalin. However, a combination of Met-enkephalin and naloxone significantly decreased the labeling indices of the colon mucosa and/or cancers. These findings indicate that Met-enkephalin enhanced colon carcinogenesis and that naloxone attenuated this enhancement. Because naloxone is an opioid receptor antagonist, these findings also indicate that the enhancing effect of Met-enkephalin on colon carcinogenesis may be mediated through opioid receptors.
 ...
PMID:Enhancement by methionine enkephalin of colon carcinogenesis induced by azoxymethane. 198 18

Cremophore E1 (CR), a frequently used solubilizer and emulsifier in the pharmaceutical, cosmetic and animal-raising industries, is made up of ethylene oxide and castor oil. Since ethylene oxide has been shown to be a potent genotoxic agent, we have studied the clastogenic activity of CR and its co-clastogenic activity with benzene (BZ) in mice. Male CD1 mice were divided into untreated, vehicle control and experimental groups. Mice in the experimental groups were treated orally with 0.03, 0.3 or 3% CR in water, 440 mg/kg BZ in olive oil, BZ plus the three different doses of CR (1 h apart) or BZ plus 3% CR separated by 1, 3 and 5 h intervals. Mice were killed at 30 h after the treatment for the single-treatment groups and after the first treatment for the combined treatment groups. Bone marrow cells were harvested for determination of micronuclei (MN) frequencies in polychromatic erythrocytes (PCE). The presence of known genotoxic metabolites of benzene (phenol and trans,trans muconic acid) was quantitated in collected urine. The effect on hepatic cytochrome P450 isoenzyme expression in livers of treated mice were also analyzed. We found that CR did not induce any significant or dose-dependent increase in MN. However, CR enhanced the clastogenic activity of BZ in a dose-dependent manner (from 41.6 to 47.3, 60.5 and 67.1 MN/1000 PCE respectively; P less than 0.05). The combined treatment showed an inverse time-dependent change in MN frequencies when CR was administered at 1, 3 and 5 h after BZ (41.6 to 67.1, 43.4 and 42.0 MN/1000 PCE respectively). The enhancement effect of CR is apparently due to its ability to induce significantly the cytochrome P450I family when CR was administered 1 h after treatment with BZ. However, no positive synergistic effect was observed when the combined treatment intervals were extended to 3 and 5 h. Enhanced induction of these isoenzymes is correlated with increased metabolic activation of BZ to excrete increased amounts of trans,trans muconic acid, the putative active metabolite of BZ, in urine. Our integrated study demonstrates that an apparently innocuous agent that is consumed by the general population can enhance the genotoxic activity of a ubiquitous environmental carcinogen. The potential existence of this type of interaction in our daily lives is frequently overlooked and should be investigated.
Carcinogenesis 1991 Jan
PMID:Mechanism of clastogenic and co-clastogenic activity of cremophore with benzene in mice. 198 82

Previous studies have shown that the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulates phagocytic leukocytes to produce reactive oxygen intermediates in vitro. The present studies focused on the production of reactive oxygen intermediates by peripheral blood leukocyte cell populations following in vivo exposure of murine epidermis to TPA. TPA induced a dose-dependent (0.2-20 micrograms) increase in polymorphonuclear cells (PMN) that appeared to be recruited from the marginal pools, while simultaneously decreasing the number of peripheral blood mononuclear cells. These alterations were detected as early as 2 h following topical application of TPA and persisted over a 21 day time period, using a twice-weekly TPA treatment schedule. The oxidation of 2',7'-dichlorofluorescin (DCFH) was used to examine the hydroperoxide production in peripheral blood PMN isolated from SENCAR mice treated with TPA. TPA stimulated a 2-fold increase in PMN-associated DCFH oxidation (645.4 +/- 118 fmol DCF) 4 h after topical application of 10 micrograms TPA when compared to PMN isolated from acetone-treated mice (339.0 +/- 35.8 fmol DCF). These observations suggest that topical application of TPA recruits PMN that are activated prior to their infiltration into the epidermis. Given the ability of these cells to migrate to local sites, they may serve as a primed cell population that significantly contributes to cutaneous alterations observed during acute and chronic inflammation following TPA exposure.
Carcinogenesis 1991 Jan
PMID:Enhanced hydroperoxide production by peripheral blood leukocytes following exposure of murine epidermis to 12-O-tetradecanoylphorbol-13-acetate. 198 87

The gastric mucin M1 antigens, markers associated with colonic carcinogenesis, have been characterized by new antimucin monoclonal antibodies (MAbs). These MAbs, obtained against mucins isolated from a human ovarian mucinous cyst (MAbs 19M1, 21M1 and 45M1) and from a pancreatic adenocarcinoma (MAb 96RA), were compared with 5 other anti-M1 mucin MAbs described previously, which characterized the a, b, c, d and e mucin M1 epitopes. Using immunoperoxidase, these new MAbs exclusively stained the surface gastric epithelium of normal human gastro-intestinal tract and reacted with fetal, precancerous and cancerous colonic mucosa, but not with normal colon. Immunoradiofixation studies showed that these new MAbs are directed against 3 epitopes (f, g and h) which are different from the a, b, c, d and e mucin M1 epitopes, though present on the same a immunoreactive high-molecular-weight components (greater than 1,000 kDa) with a density of 1.4 by CsCl-density-gradient ultracentrifugation. M1 antigenicity is characterized by a family of 8 different M1 epitopes which were destroyed with beta-mercaptoethanol (except for the f epitope), sensitive to a 5 hr trypsin treatment and resistant to 5 mM periodate (except for the h epitope). Some epitopes (b, c and d) showed increasing immunoreactivity after 20 mM periodate treatment, suggesting cryptic location. In rat-colon adenocarcinomas, M1 mucin epitopes were masked but could be decrypted using high periodate treatment, similar to normal rat gastric mucosa, thus suggesting the absence of drastic changes in the saccharide coat of the peptide mucin portion bearing M1 epitopes. Cryptic location, periodate resistance, sensitivity to protease and conformational behavior strongly suggest that the peptidic core of gastric (or fetal colonic) mucin plays a role in M1 immunoreactivity. Indeed, the resurgence of M1 antigens during colonic carcinogenesis is due to re-expression of the peptide core of gastric (or fetal colonic) mucins.
 ...
PMID:Oncofetal mucin M1 epitope family: characterization and expression during colonic carcinogenesis. 198 72


<< Previous 1 2 3 4 5 6 7 8 9 10