Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male Ah-responsive C57BL/10ScSn mice received a single dose of iron-dextran (600 mg Fe/kg) and were fed a diet containing 0.01% of the PCBs mixture Aroclor 1254 for up to 12 months. Iron caused a marked synergistic increase in liver size from 2 months with greatly elevated mitotic rates, numbers of basophilic foci and incidences of bile duct and oval cell proliferation. Although at 4 months much of the liver enlargement was due to iron-depleted hyperplastic regions and lipid accumulation, by 8 months seven out of nine mice had nodules (hepatocellular adenomas) whereas none were observed in the Aroclor alone group. After 12 months, 16 out of 18 mice had multiple nodules and/or hepatocellular carcinomas whereas only one of 16 mice was positive in a group not given iron. Basophilic nodules were more common than clear cell nodules in those mice with carcinomas than in those animals without. Preloading with iron also greatly enhanced the development of cholangiofibrosis at 8 and 12 months. Preliminary experiments with the polybrominated biphenyl mixture Firemaster BP-6 indicated a similar synergistic interaction with iron. No effects of iron and Aroclor 1254 on the liver were observed in the Ah-nonresponsive strain DBA/2. Iron potentiated the development of uroporphyria after exposure to those chemicals in C57BL/10ScSn mice but not in the DBA/2 mice. Therefore in C57BL/10ScSn mice the carcinogenicity of PCBs and possibly PBBs, is modulated by iron status and probably not at a late stage where these chemicals may act in a promotional manner.
Carcinogenesis 1990 Mar
PMID:Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice. 215 20

Inbred strains of mice were found to differ significantly in their susceptibility to liver tumor promotion by PB. The susceptibility to promotion of hepatocarcinogenesis by this drug was a dominant trait in crosses between the sensitive DBA and resistant C57 mice. The reciprocal F1 hybrids responded similarly to tumor promotion by PB. PB promoted the development of hepatoblastomas in D2B6F1 males but not in B6D2F1 mice. Female mice of the D2B6F1 cross, similarly exposed to PB, failed to develop hepatoblastomas. These results suggested a sex-linked differential response to the development of hepatoblastomas in reciprocal F1 hybrids that are genetically identical except for the reverse origin of their X and Y chromosomes. Differences in the promoting effects of PB between C57 and DBA mice appeared to correlate with differences in the metabolism/detoxification of this drug. In conclusion, mouse strains that differ in susceptibility to two-stage liver carcinogenesis provide excellent opportunities to investigate the genetic and/or biochemical mechanisms responsible for these differences. Understanding these mechanisms may lead to the identification of factors that affect liver tumor development not only in mice but in other species as well.
 ...
PMID:Strain-dependent effects of phenobarbital on liver tumor promotion in inbred mice. 217 66

The 4S polycyclic aromatic hydrocarbon (PAH)-binding protein (PBP) is a cytoplasmic protein that binds PAHs with specificity and high affinity. We have used antisera for the PBP and unlabeled peroxidase anti-peroxidase immunohistochemistry to demonstrate its possible localization in cell types known to have xenobiotic metabolizing capabilities. Cellular sites of the PBP in liver, lung and kidney of C57BL/6 and DBA/2 mice were probed. The PBP was visualized in hepatocytes throughout the liver lobule and was not preferentially located in either centrilobular or periportal areas. However, cellular heterogeneity with respect to PBP content was clearly evident in the hepatocyte population. The positive reactivity correlated with substantial levels of benzo[a]pyrene (B[a]P) binding in liver cytosol. In the lung, the PBP was found in the bronchiolar epithelium and the alveolar septa, and was localized in ciliated and non-ciliated Clara and alveolar type II cells as well as in alveolar macrophages. In the kidney, the glomeruli and epithelia of proximal and distal convoluted tubules and collecting ducts were labeled. Staining for the PBP was greatest in the apical region of the pyramid and was localized in the epithelial lining of the collecting ducts. Relatively lower levels of the PBP were detected in the lung and kidney than in the liver. Staining was localized in the cytoplasmic compartment of cells in all tissues examined. Similar immunoreactivities were exhibited in the tissues of both C57BL/6 and DBA/2 mice. Treatment with beta-naphthoflavone (beta NF) altered neither the intensity nor pattern of immunostaining. Furthermore, treatment with beta NF or isosafrole has no effect on the Kd and Bmax of B[a]P binding to liver cytosolic PBP. The results of our experiments demonstrate localization of the PBP to sites of active physiological response to PAH exposure.
Carcinogenesis 1990 Oct
PMID:The 4S polycyclic aromatic hydrocarbon-binding protein: immunohistochemical localization in mice. 220 97

All tumor-promoting phorbol esters induce inflammation in mouse skin. The correlation between promoting and inflammatory activities is only partial, however, indicating that only some events in inflammation may be closely coupled to the process of tumor promotion. Resiniferatoxin (RTX), an extremely inflammatory phorbol-related diterpene, acts as an ultrapotent analog of capsaicin to stimulate and then to block the neurogenic inflammatory pathway. In CD-1 mice, we have used pretreatment with RTX to show that the erythema and edema responses to phorbol and 12-deoxyphorbol esters in significant part involve this neurogenic inflammatory pathway. We report here that mouse strains with differing sensitivities to phorbol-ester-induced promotion displayed marked differences in the effect of pretreating with RTX on the edema response following phorbol-12-myristate-13-acetate (PMA) application. In the highly promotion-sensitive SENCAR mouse, RTX pretreatment had little inhibitory effect; the edema response to PMA was similar with or without RTX pretreatment 6 h before PMA application. On the other hand, in C57BL/6J mice, which are resistant to promotion by phorbol esters under the usual protocols, the edema response to PMA was totally eliminated by RTX pretreatment during the first 8 h after PMA administration. DBA/2J mice, which are similar to CD-1 mice in their susceptibility to PMA promotion, responded similarly to CD-1: the edema response was blocked partially by RTX pretreatment during the early phase (up to 8 h) of inflammation. Our results suggest that the RTX-resistant component of PMA-induced edema may correlate better with the sensitivity to promoting action than does the overall inflammatory response.
Carcinogenesis 1990 Apr
PMID:Effect of resiniferatoxin pretreatment on the inflammatory response to phorbol-12-myristate-13-acetate in mouse strains with different susceptibilities to phorbol ester tumor promotion. 232 99

The induction of transplacental carcinogenesis by 3-methylcholanthrene (MC) in mice is determined, in part, by the genotype at the Ah locus. The relationship of Ah genotype and MC-induced DNA adducts was tested by comparing the response of pregnant and fetal C57BL/6 mice (Ahb Ahb; responsive to the induction of MC metabolism) and DBA/2mice (Ahd Ahd; nonresponsive). On day 17 of gestation (day 1 = presence of vaginal plug), C57BL/6 mice were treated i.p. with 100 mg/kg MC and DBA/2 mice with 30 mg/kg. Mice were sacrificed 24 h later and the tissues were analyzed for the presence of DNA adducts using the P1 nuclease version of the 32P-postlabeling method. With a 3.3-fold difference in administered dose, the total adduct levels in fetal DNA were (a) similar in both strains with the exception of liver, for which C57BL/6 mice had more adducts; (b) higher in the lung than skin, liver, or thymus; and (c) only 1/4 to 1/14 of the adult levels. Maternal DBA/2DNA contained more adducts in the thoracic lymph nodes and liver but fewer in the placenta and lung, compared to maternal C57BL/6 DNA. More adducts were detected in lung DNA than liver DNA in C57BL/6 mice. In contrast, these levels were similar in DBA/2 mice. When the difference in dose administered was considered in conjunction with this, less MC bound to DNA of C57BL/6 than DBA/2 mice overall. To identify adducts, oxidized metabolites of MC, 1-hydroxy-, 2-hydroxy-, 9,10-dihydrodiol-, or 3-methoxymethyl-MC, were topically applied to the dorsal skin of both strains. All of these metabolites produced adducts. Approximately 14 different adduct spots were detected. The two most abundant adducts were produced by 1-hydroxy-, 2-hydroxy-, and 9,10-dihydrodiol-MC. One of these also contained a 3-hydroxymethyl group. Several adducts did not contain the 9,10-dihydroxy group. The adducts derived from 3-methoxymethyl-MC were consistently found in greater abundance in DNA from C57BL/6 tissues, compared with DBA/2. Thus, oxidation of the 3-methyl group may be enhanced by Ah-dependent induction of MC metabolism. Together, these results suggest that the individual and total adduct levels are influenced by the genotype at the Ah locus, the route of administration, and the metabolite(s) with tissue and age specificity.
 ...
PMID:Age-, tissue-, and Ah genotype-dependent differences in the binding of 3-methylcholanthrene and its metabolite(s) to mouse DNA. 236 82

We investigated 5-azacytidine and five of its analogues for: (1) carcinogenicity, in the male Fischer rat; (2) toxicities using changes in rat weights in vivo and a cytotoxicity assay in vitro; and (3) haemoglobin gene expression, using minor haemoglobin synthesis in sheep, mice and rats. 5-Azacytidine was found to be a complete carcinogen. It increased the incidence of testicular tumours as well as non-testicular tumours in rats treated for 12 months. 5-Azacytidine also had hepatic tumour promoting properties and was able to induce transplacental carcinogenesis when administered to pregnant rats on day 21 of timed pregnancies. None of the other 5 analogues that were tested appeared to be carcinogenic in small experiments. All the analogues which are known to have hypomethylating activity were found to be cytotoxic in vitro; the most potent being 5-azacytidine. As judged by decreased rat weight compared to untreated controls, the fluorinated cytidine analogues and 5'-deoxyazacytidine were more toxic than 5-azacytidine. Altered haemoglobin synthesis was seen in rats and DBA/2J mice, but not in sheep. In mice, where the clearest haemoglobin changes were noted, an increase in minor haemoglobin synthesis was found using both high and low doses of 5-azacytidine, and with 5,6-dihydro-5-azacytidine and 5-aza-2'-deoxycytidine. These last two analogues appear to be relatively non-toxic, noncarcinogenic in these experiments, and retain haemoglobin activating properties with a potency similar to that of 5-azacytidine.
 ...
PMID:Carcinogenicity and haemoglobin synthesis induction by cytidine analogues. 245 32

Previous studies have shown that the incidences of liver and lung tumors in mice exposed transplacentally to 3-methyl-cholanthrene (MC) were significantly influenced by the sensitivity of both mothers and fetuses to induction of cytochrome(s) P-450 by polycyclic aromatic hydrocarbons. In order to delineate further the biochemical and molecular processes underlying the observed biological effects, the inductive effect of MC and beta-naphthoflavone (beta NF) on cytochrome P-450 was determined at the biochemical and molecular levels. C57BL/6 females were mated with DBA/2 males and treated i.p. on day 17 of gestation with olive oil alone, 150 mg/kg of beta NF or different doses of MC. At various times after injection the mothers were sacrificed and the fetuses removed for biochemical and molecular studies. MC caused maximal induction of aryl hydrocarbon hydroxylase (AHH) activity by 8 h in both the liver and lung. beta NF caused nearly maximal induction of AHH activity by 8 h in the lung but had little effect on liver AHH activity at this time. Maximal induction with beta NF occurred by 24 h in both organs. Addition of monoclonal antibody 1-7-1, specific for the MC-inducible forms of cytochrome P-450 (P-450IA1 and A2), to the incubation mixtures resulted in a 55-70% inhibition of AHH activity in both lung and liver assays, regardless of the inducing agent used, while having no effect on AHH activity from oil-treated mice. RNA blot analysis carried out in parallel with enzyme assays demonstrated that the levels of enzyme activity correlated very well with the levels of steady-state RNAs. MC caused maximal induction of P-450IA1 RNA levels 4 h after injection in both organs and a biphasic secondary increase was observed in the lung. Maximal levels of P-450IA1 RNA were seen at 12-16 h following injection of beta NF. However, the ratio of P-450IA1 RNAs present at 16 versus 2 h in the beta NF-treated liver appeared greater than that in the lung. P-450IA2 was also induced in fetal liver and lung, but at low levels relative to P-450IA1. The results indicate that the increase in functional AHH activity was primarily due to induction of cytochrome P-450IA1. The differences in induction kinetics observed for cytochromes P-450IA1 and A2 suggest that these enzymes exhibit both tissue- and inducer-dependent specificity.
Carcinogenesis 1989 May
PMID:Differential induction of fetal mouse liver and lung cytochromes P-450 by beta-naphthoflavone and 3-methylcholanthrene. 246 28

In order to analyze the genetics of susceptibility to promotion of hepatocarcinogenesis in DBA/2NCr and C57BL/6NCr mice by phenobarbital (PB), reciprocal F1 hybrid male mice were given 90 mg N-nitrosodiethylamine (NDEA)/kg body weight, i.p. at 5 weeks of age followed by 0.05% PB in drinking water. Hepatocellular adenomas and carcinomas were comparably increased in incidence and multiplicity in both reciprocal hybrids over mice given NDEA alone. Eight of 10 D2B6F1 progeny of DBA/2NCr females mated with C57BL/6NCr males, but only 1/10 B6D2F1 mice (progeny of C57BL/6NCr females mated with DBA/2NCr males) given PB after NDEA initiation developed single or multiple hepatoblastomas within 42 weeks. These small-celled, intensely basophilic tumors were characteristically hemorrhagic and highly malignant. Hepatoblastomas were mostly found within or adjacent to hepatocellular tumors. No hepatoblastomas were seen in either hybrid given NDEA alone. PB consistently enhanced development of malignant hepatoblastomas, as well as promoted hepatocarcinogenesis in D2B6F1 males, but did not elicit hepatoblastoma development in B6D2F1 males that were genetically identical to D2B6F1 males except for the reverse origin of their X and Y chromosomes.
Carcinogenesis 1989 Jul
PMID:Promotion of malignant 'embryonal' liver tumors by phenobarbital: increased incidence and shortened latency of hepatoblastomas in (DBA/2 x C57BL/6)F1 mice initiated with N-nitrosodiethylamine. 247 33

Inbred mouse strains that differing widely in their susceptibility to multistage skin carcinogenesis provide useful models for studying the genetic factors involved and advancing our understanding of the biochemical and molecular events associated with this process. The process of skin tumor initiation appears to be somewhat similar in various strains of mice, and most data in the literature suggest that differences in response to skin tumor promoters are a major determinant in controlling susceptibility to multistage skin carcinogenesis. A model system has been developed for examining the genetics of susceptibility to skin tumor promotion. The susceptibility to phorbol ester skin tumor promotion in crosses between DBA/2 and C57BL/6 mice is inherited as an incomplete dominant trait, and neither X-chromosome nor cytoplasmic genetic determinants appear to play a major role in determining susceptibility in these two inbred strains. In addition, two or more genetic loci contribute to the higher sensitivity of DBA/2 mice than C57BL/6 mice to TPA-induced skin tumor promotion. Further studies to characterize these genes will contribute greatly to our understanding of the mechanisms of phorbol ester skin tumor promotion. In addition, much work should now be directed at understanding the cellular, biochemical, and molecular mechanisms for differential responsiveness not only to phorbol esters but also to other classes of tumor promoters.
 ...
PMID:Genetic background and development of skin tumors. 249 34

Qualitative changes of glycoconjugates in luminal surface and goblet cell mucin from colon mucosa of 1,2-dimethylhydrazine (DMH)-treated rats were studied. Eight fluoresceinated lectins were used: Dolichos biflorus (DBA), Glycine max (SBA), Triticum vulgare (WGA), Limax flavus (LFA), Arachis hypogaea (PNA), Griffonia simplicifolia-I (GS-I), Ulex europaeus-I (UEA-I) and Canavalia ensiformis (Con A). The lectin-binding patterns were studied in tumors arising in proximal and distal portions of the colon, in transitional mucosa (TM) and in mucosa distant from tumors. Lectin reactivity observed in mucosa of DMH-treated rats was compared with that obtained in colon mucosa of control rats. In tumors and non-neoplastic mucosa of DMH-treated rats the reactivity of DBA, SBA, WGA, LFA, GS-I and Con A were similar to that in the mucosa of control rats. In contrast, important changes were observed in the reactivity of UEA-I and PNA. Contrary to the staining in the control mucosa, UEA-I bound intensely to all carcinomas and PNA to 50% and 60% of carcinomas arising in proximal and distal colon, respectively. Moreover, in TM and mucosa distant from tumors, UEA-I and PNA also differed in their binding patterns to that obtained in the colonic mucosa of the control rats. UEA-I- and PNA-binding to luminal surface and UEA-I-binding to the mucin of distal colonic mucosa from DMH-treated rats was similar to that observed in rat fetal colon suggesting a reappearance of a fetal-type pattern. Contrarily, PNA-reactivity in goblet cell and carcinoma mucin is a unique feature of colonic carcinogenesis not present during fetal development.
 ...
PMID:Lectin-binding sites in neoplastic and non-neoplastic colonic mucosa of 1,2-dimethylhydrazine-treated rats. 268 74


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