Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been postulated that inducers of UDP-glucuronosyltransferase (UGT) decrease circulating thyroid hormone concentrations by increasing their biliary excretion. The inducers pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are each effective at reducing serum thyroxine concentrations. However, only PCN treatment produces a marked increase in serum levels of thyroid-stimulating hormone (TSH), whereas 3MC and PCB cause little to no increase in TSH. Excessive TSH elevation is considered the primary stimulus for thyroid tumor development in rats, yet the mechanism by which enzyme induction leads to TSH elevation is not fully understood. Whereas PCN, 3MC, and PCB all increase microsomal UGT activity toward T(4), only PCN causes an increase in T(3)-UGT activity in vitro. The purpose of this study was to determine whether PCN, which increases serum TSH, causes an increase in the glucuronidation and biliary excretion of T(3) in vivo. Male rats were fed control diet or diet containing PCN (1000 ppm), 3MC (250 ppm), or PCB (100 ppm) for 7 days. Animals were then given [(125)I]-T(3), i.v., and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with gamma-detection. The biliary excretion of total radioactivity was increased up to 75% by PCN, but not by 3MC or PCB. Of the T(3) excreted into bile, approximately 75% was recovered as T(3)-glucuronide, with remaining amounts represented as T(3)-sulfate, T(2)-sulfate, T(3), and T(2). Biliary excretion of T(3)-glucuronide was increased up to 66% by PCN, while neither 3MC nor PCB altered T(3)-glucuronide excretion. These findings indicate that PCN increases the glucuronidation and biliary excretion of T(3) in vivo, and suggest that enhanced elimination of T(3) may be the mechanism responsible for the increases in serum TSH caused by PCN.
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PMID:Effect of microsomal enzyme inducers on the biliary excretion of triiodothyronine (T(3)) and its metabolites. 1181 22

EFT is defined by the expression of ews/ets fusion genes. The type of the fusion transcript impacts on the clinical biology. EFT requires risk adapted treatment. A risk-adapted treatment is determined by tumor localisation, tumor stage and volume. For metastatic and relapsed disease the pattern of spread and the time of relapse are the determinants of risk stratification. Staging of Ewing tumors has been considerably improved by magnetic resonance imaging and modern isotope scanning techniques. However, the determination of the extent of the metastatic spread in particular number of involved bones remains an unresolved issue. The prognosis for high-risk Ewing tumors has been improved by multimodal and high-dose radio/chemotherapy (HDC). The concepts for high-dose therapy in Ewing tumors are based on dose response and dose intensity relationships. In single agent HDC most experience exists with Melphalan. Several chemotherapeutic agents have been used in combination HDC with or without TBI such as Adriamycin, BCNU, Busulphan, Carboplatin, Cyclophosphamide, Etoposide, Melphalan, Thiotepa Procarbazin and Vincristine. To date, superiority of any high-dose chemotherapy regimen has not been established. However, the clinical biology, the pattern of spread and the time of relapse determine the prognosis of patient who are eligible for HDC. In particular, patients with multifocal bone or bone marrow metastases have a poorer prognosis than patients with lung metastases. In addition, patients with a relapse within 24 months have a poorer prognosis than patients with a relapse later than 24 months after diagnosis. This review will analyze the results of single- and multi-agent chemotherapy with respect to agent combination, dose and risk stratum of patient population. Future therapeutic modalities for the treatment of EFT might encompass immunotherapeutic and genetic strategies including allogeneic stem cell transplantation.
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PMID:High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT). 1185 93

This study evaluates and quantifies the interactive hepatic tumor promoting effects of two PCBs, the Ah receptor agonist PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the constitutive androstane receptor (CAR) agonist PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl). Promotion of altered hepatic foci was evaluated utilizing a medium-term 8-week bioassay for promoters of hepatocarcinogenesis. The assay employs placental glutathione-S-transferase positive (GST-P+) liver cell foci as markers of preneoplasia in female Fischer 344 rats treated with the known initiator diethylnitrosamine followed by partial hepatectomy and by gavage exposure to test chemicals. GST-P+ foci were quantified by histomorphometry and were reported as areas and numbers of GST-P+ foci within the area of liver examined. For PCB 126, the doses were 0.1, 1.0, and 10 microg/kg body weight. For PCB 153, the doses were 10, 100, 1000, 5000, and 10,000 microg/kg body weight. Combined PCB 126 and 153 exposures were 0.1 + 10, 1 + 100, 10 + 1000, 10 + 5000, and 10 + 10,000 microg/kg, respectively. Individual PCB treatment resulted in dose dependent increases in liver and adipose concentrations. Hepatic PCB 153 levels were significantly increased (p < 0.01) after combined exposure. Treatment with PCB 126 or PCB 153 alone resulted in a significant (p < 0.01) dose dependent increase in GST-P+ foci area and number compared with controls. Treatment with the mixture of PCB 126 and 153 resulted in antagonistic GST-P+ focus formation (p < 0.001) for both foci area and number. The less than additive effect was present at all 5 PCB 126/PCB 153 dose combinations, including the low doses of PCB 126 and 153 that did not show significant promotional activity alone.
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PMID:Nonadditive hepatic tumor promoting effects by a mixture of two structurally different polychlorinated biphenyls in female rat livers. 1186 72

Arylhydrocarbon receptor knock-out, AhR(-/-), mice have recently been shown to be rather resistant to benzo[a]pyrene (B[a]P)-induced tumor formation, probably reflecting the inability of these mice to express significant levels of cytochrome P450 (P450 or CYP) 1A1 that activates B[a]P to reactive metabolites (Y. Shimizu, Y. Nakatsuru, M. Ichinose, Y. Takahashi, H. Kume, J. Mimura, Y. Fujii-Kuriyama and T. Ishikawa (2000) PROC: Natl Acad. Sci. USA, 97, 779-782). However, it is not precisely determined whether CYP1B1, another enzyme that is also active in activating B[a]P, plays a role in the B[a]P carcinogenesis in mice. To understand the basis of roles of CYP1A1 and CYP1B1 in the activation of chemical carcinogens, we compared levels of induction of liver and lung CYP1A1, 1A2, and 1B1 by various polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls in AhR(+/+) and AhR(-/-) mice. Liver and lung CYP1A1 and 1B1 mRNAs were highly induced in AhR(+/+) mice by a single intraperitoneal injection of each of the carcinogenic PAHs, such as B[a]P, 7,12-dimethylbenz[a]anthracene, dibenz[a,l]pyrene, 3-methylcholanthrene, 1,2,5,6-dibenzanthracene, benzo[b]fluoranthene, and benzo[a]anthracene and by a co-planar PCB congener 3,4,3',4'-tetrachlorobiphenyl. We also found that 6-aminochrysene, chrysene, benzo[e]pyrene, and 1-nitropyrene weakly induced the mRNA expression of CYP1A1 and 1B1, whereas anthracene, pyrene, and fluoranthene that have been reported to be non-carcinogenic in rodents, were very low or inactive in inducing these P450s. The extents of induction of liver CYP1A2 by these chemicals were less than those of CYP1A1 and 1B1 in AhR(+/-/+/-) mice. In AhR(-/-) mice, there was no induction of these P450s by PAHs and polychlorinated biphenyls. Liver microsomal activities of 7-ethoxyresorufin and 7-ethoxycoumarin O-deethylations and of mutagenic activation of (+/-)-trans-7,8-dihydroxy-7,8-dihydro-B[a]P to DNA-damaging products were found to correlate with levels of CYP1A1 and 1B1 mRNAs in the liver. Our results suggest that carcinogenicity potencies of PAHs may relate to the potencies of these compounds to induce CYP1A1 and 1B1 through AhR-dependent manner and that these induced P450s participate in the activation of B[a]P and related carcinogens causing initiation of cancers in mice.
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PMID:Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6J mice. 1211 79

Whether environmental contaminants increase breast cancer risk among women on Long Island, NY, is unknown. The study objective is to determine whether breast cancer risk is increased in relation to organochlorines, compounds with known estrogenic characteristics that were extensively used on Long Island and other areas of the United States. Recent reports do not support a strong association, although there are concerns with high risks observed in subgroups of women. Blood samples from 646 case and 429 control women from a population-based case-control study conducted on Long Island were analyzed. No substantial elevation in breast cancer risk was observed in relation to the highest quintile of lipid-adjusted serum levels of p,p'-bis(4-chlorophenyl)-1,1-dichloroethene (DDE) [odds ratio (OR), 1.20 versus lowest quintile; 95% confidence interval (CI), 0.76-1.90], chlordane (OR, 0.98; 95% CI, 0.62-1.55), dieldrin (OR, 1.37; 95% CI, 0.69-2.72), the sum of the four most frequently occurring PCB congeners (nos. 118, 153, 138, and 180; OR, 0.83; 95% CI, 0.54-1.29), and other PCB congener groupings. No dose-response relations were apparent. Nor was risk increased in relation to organochlorines among women who had not breastfed or were overweight, postmenopausal, or long-term residents of Long Island; or with whether the case was diagnosed with invasive rather than in situ disease, or with a hormone receptor-positive tumor. These findings, based on the largest number of samples analyzed to date among primarily white women, do not support the hypothesis that organochlorines increase breast cancer risk among Long Island women.
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PMID:Environmental toxins and breast cancer on Long Island. II. Organochlorine compound levels in blood. 1216 20

In the present study, a series of 32 hydroxy- and dihydroxy-polychlorinated biphenyls (OH-PCBs) and PCB-derived quinones were prepared and evaluated for their in vitro potencies to downregulate gap junctional intercellular communication (GJIC) and to activate the aryl hydrocarbon receptor (AhR) and the estrogen receptor alpha (ER) in well-established liver and mammary cell models. The rat liver epithelial cell line WB-F344 was used for in vitro determination of GJIC inhibition; the AhR-inducing activity was determined in the rat hepatoma H4IIE.Luc cells stably transfected with a luciferase reporter gene; ER-mediated activity was measured in two breast carcinoma cell lines, MVLN and T47D.Luc, stably transfected with luciferase under the control of estrogen responsive element. Acute inhibition of GJIC, potentially associated with tumor promotion, was detected after treatment with all OH-PCBs under study, with the persistent OH-PCBs being the strongest ones. Several compounds were found to significantly induce the AhR-mediated activity, including 4'-OH-PCB 79, a metabolite of PCB 77, and 2-(4'-chloro)- and 2-(3',4'-dichloro)-1,4-benzoquinones and 1,4-hydroquinones. Low molecular weight OH-PCBs, such as 3'-hydroxy, 4'-, and 3',4'-dihydroxy-4-chlorobiphenyl, elicited significant estrogenic activity and potentiated effect of 17beta-estradiol. Antiestrogenic potencies, determined in the presence of 17beta-estradiol, were found for persistent 4-OH-PCB 187, 4-OH-PCB 146, and some low chlorinated PCB derivatives. However, no apparent association between induction of AhR activity and antiestrogenicity was observed. The majority of the OH-PCBs suppressed the 17beta-estradiol response only at cytotoxic concentrations. Spearman's rank correlations were calculated for these biological data and the physicochemical descriptors, hydrophobicity (log P), molar volume, pKa, log D, and dihedral angle. Significant correlations were found between potency to downregulate GJIC and log P and molar volume (R = -0.7, p < 0.0001). Antiestrogenic effects were also negatively correlated with hydrophobicity and molar volume. No significant correlations among other biological end points and the physicochemical descriptors were observed for the entire set of compounds. These results show that oxygenated PCB metabolites are capable of multiple adverse effects, including gap junction inhibition, AhR-mediated activity, and (anti)estrogenicity. The inhibition of GJIC by OH-PCBs represents a novel mode of action of both the lower chlorinated and the persisting high molecular weight OH-PCBs.
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PMID:Toxicity of hydroxylated and quinoid PCB metabolites: inhibition of gap junctional intercellular communication and activation of aryl hydrocarbon and estrogen receptors in hepatic and mammary cells. 1502 4

We attempted to prevent spontaneous development of liver tumors by s.c. inoculation with DCs loaded with syngeneic HCC cells in C3H/HeNCrj mice. A new cell line, MIH-2, was established from an HCC that had developed spontaneously in a C3H/HeNCrj mouse. Bone marrow-derived DCs were loaded with irradiated MIH-2 cells by treatment with PEG. Fluorescence microscopy and flow-cytometric analysis showed that about 45% of PEG-treated DCs and MIH-2 cells (DC/MIH-2) were DCs loaded with MIH-2 cells. Thirteen-month-old mice received inoculations of DC/MIH-2 (9 x 10(5)/mouse) 4 times at 6-day intervals and were killed at 16 months of age to assess liver tumors. The incidence of liver tumors in these mice was significantly lower than that in mice not receiving inoculations (p < 0.05) but similar to that in 13-month-old mice (the age at which inoculation started), indicating that inoculation inhibited the development of new tumors. Splenocytes from inoculated mice, but not those from uninoculated mice, showed cytotoxic activity against MIH-2 cells. Cytotoxic activity was not elicited by CD4(+) T cells, CD8(+) T cells, or DX5(+) cells isolated from splenocytes but was elicited by adherent cells, identified as CD11b(+) macrophages. CD4(+) T cells, but not CD8(+) T cells, from inoculated mice produced IFN-gamma by incubation with DC/MIH-2. Cytotoxicity by splenocytes was attenuated by anti-IFN-gamma antibody. Immunization with DCs loaded with syngeneic HCC cells induces CD4(+) T cells that produce IFN-gamma by response to antigen of HCC, which would lead to macrophage activation to kill liver tumor cells at an early stage.
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PMID:Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice. 1519 77

Pregnenolone-16alpha-carbonitrile (PCN) and Aroclor 1254 (PCB) both reduce serum thyroid hormone levels in rats, but only PCN consistently produces an increase in serum thyrotropin (TSH). PCN-mediated increases in TSH result in increased thyroid follicular cell proliferation and hyperplasia, which may represent early events on a morphological continuum leading to neoplasia. The purpose of this study was to assess whether PCN, a compound that increases serum TSH, and PCB, which does not increase TSH, promote thyroid tumors in a two-stage carcinogenesis model. Male SD rats were administered the thyroid tumor initiator diisopropanolnitrosamine (2.5 g/kg, sc), and after seven days were fed control diet, diet containing 1000 ppm PCN, or diet containing 100 ppm PCB for 19 weeks. Body weights were unaffected by PCN treatment, but were reduced 21% after 19 weeks of PCB treatment compared to control. PCN treatment significantly reduced serum T4 through week 3 before returning to control concentrations, whereas T4 levels following PCB treatment fell below detection limits by week 3 and remained drastically reduced through week 19. TSH concentrations in PCN-treated rats increased three-fold at week 2, then declined to near control values at week 19. After one week of PCB treatment, TSH concentrations reached nearly twice that of controls, and were sustained until week 6. The incidence of thyroid follicular cell proliferative lesions, including cystic and follicular hyperplasia, cystic and follicular adenoma, and follicular carcinoma, was significantly increased following PCN treatment, but not following PCB treatment. PCB treatment caused an increase in thyroid carcinomas (4 of 22 rats) not associated with the proliferative-type lesions produced by PCN, despite an increase in TSH serum concentrations. In conclusion, PCN appears to promote thyroid tumors in a manner consistent with known effects of excessive TSH stimulation. However, thyroid carcinomas stemming from PCB treatment indicate that separate mechanisms exist for the production of thyroid cancer in rodents by chemicals classically considered microsomal enzyme inducers.
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PMID:Promotion of thyroid tumors in rats by pregnenolone-16alpha-carbonitrile (PCN) and polychlorinated biphenyl (PCB). 1520 39

In this study, the effect of dietary vitamin E on the hepatic tumor-promoting activity of PCB-77 and PCB-153 in female Sprague-Dawley rats (175-200 g) was investigated. One week after diethylnitrosamine injection, rats were fed purified diets containing 10, 50, or 250 mg/kg vitamin E in the form of alpha-tocopheryl acetate. Starting 1 wk later, we injected rats i.p. with vehicle (corn oil) or PCB-77 or PCB-153 (300 mumol/kg) every 14 d for 4 injections. All rats were killed 10 d after the last PCB injection. The number and volume of placental glutathione S-transferase (PGST)-positive foci were increased by PCB-77 but not by PCB-153. Vitamin E did not affect the induction of PGST-positive foci. PCB-77, but not PCB-153, increased hepatic NF-kappaB activity. In conclusion, dietary vitamin E supplementation does not protect against the induction of altered hepatic focal lesions by PCBs.
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PMID:Dietary vitamin E does not inhibit the promotion of liver carcinogenesis by polychlorinated biphenyls in rats. 1567 Dec 27

The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2',4',6'-trichloro-4-biphenylol (OH-PCB-30) and 2',3',4',5'-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor alpha. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 microg/day) or 17beta-estradiol (5 microg/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds.
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PMID:Long-term effects of neonatal exposure to hydroxylated polychlorinated biphenyls in the BALB/cCrgl mouse. 1607 73


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