UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor promoting activity of 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) was studied in an initiation/promotion bioassay in female Sprague-Dawley rats initiated with N-nitrosodiethylamine after partial hepatectomy. PCB 156 (50, 300, 1500, or 7500 microg/kg body weight/week) was administered by once-weekly subcutaneous injections for 20 weeks. Some high dose animals were left without treatment for an additional 20 weeks to study posttreatment effects. The volume fraction of the liver occupied by glutathione S-transferase P-positive foci was significantly increased to 2.9, 3.3, and 12% at 300, 1500, and 7500 microg/kg body weight/week, respectively, compared to 1.2% in the controls. The volume fraction was 43% in the high dose group 20 weeks after treatment was stopped, probably reflecting the slow body clearance of PCB 156 as indicated by the sustained liver and adipose tissue concentrations. Treatment with PCB 156 following initiation caused decreased body weight gain, thymic atrophy, liver enlargement, induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities, histopathological effects, and increased activities of aspartate aminotransferase and gamma-glutamyltransferase in plasma. These results show that PCB 156 can enhance the growth of altered foci in rat liver and probably act as a tumor promoter of hepatocarcinogenesis. Based on promotional activity a relative potency of PCB 156 to 2,3,7, 8-tetrachlorodibenzo-p-dioxin of 0.0001-0.001 is proposed.
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PMID:Promotion of enzyme altered foci in female rat 2,3,3',4,4',5-hexachlorobiphenyl. 935 6

Both increased cell proliferation and "altered" CYP gene expression are prominent phenomena associated with liver tumor promotion by nongenotoxic carcinogen treatment. To further characterize these two responses, groups of rats were kept on powdered rat chow diet containing 0.05% phenobarbital (PB) or 0.025% ciprofibrate (Cip) for 8 days or given 8 daily doses by gavage of pregnenolone 16 alpha-carbonitrile (PCN, 150 mg/kg/ml corn oil), 3,3',4,4'-tetrachlorobiphenyl (PCB-MC, 3 mg/kg/ml corn oil) or 2,2',4,4'-tetrachlorobiphenyl (PCB-PB, 7.5 mg/kg/ml corn oil). A minipump was implanted in the rat abdominal cavity to release bromodeoxyuridine (BRDU) 5 days after the start of nongenotoxic carcinogen treatment and the experiment was terminated 3 days later. BRDU-labeled parenchymal nuclei were observed primarily in the periportal area independent of nongenotoxic carcinogen treatment. Treatment with each of the 5 nongenotoxic carcinogens resulted in profound alterations in CYP gene expression at both the transcriptional and translational levels. Expression of CYP1A1, 1A1/2, 3A1, 2B1/2, and 4A immunoproteins demonstrated nongenotoxic carcinogen-specific patterns in both magnitude and zonal distribution. In agreement with the CYP immunoprotein data, treatment with each of the five nongenotoxic carcinogens resulted in a unique composition of mRNAs of CYP2B1, 2B2, 2C6, 2C11, 3A1, 3A2, and 4A1, which were variably increased or decreased relative to the untreated control livers, depending on the treatment. Similarly, the rate and pattern of CYP enzyme-mediated hydroxylation toward testosterone, 17 beta-estradiol, corticosterone, and lauric acid were greatly altered by nongenotoxic carcinogen treatment. According to the zonal distribution patterns of CYP immunoproteins, each hepatocyte in the cell plate from the periportal triad to the central vein has a characteristic and nongenotoxic carcinogen-specific composition of CYP enzymes. Because many endogenous substrates are modulators of DNA and RNA synthesis, intracellular kinetics of endogenous substrates of CYP enzymes in the corresponding hepatocytes could contribute, at least in part, to the differences in gene expression, differentiation, and cell proliferation among the hepatocytes in the cell plate.
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PMID:Zonal differences in DNA synthesis activity and cytochrome P450 gene expression in livers of male F344 rats treated with five nongenotoxic carcinogens. 937 37

The assessment of the carcinogenic risk of polychlorinated dioxins (PCDDs), furans (PCDFs), and biphenyls (PCBs) by TEFs is hampered by species- and tissue-specific responses that cannot readily be explained by differences in the Ah receptor levels but may be due to events subsequent to ligand binding to the Ah receptor. Moreover, PCDDs and related compounds accumulate in the environment, in animal and human tissues as highly complex mixtures. Thus, comprehensive risk assessment should include all Ah receptor ligands and agents that modulate the Ah receptor-mediated responses. Tumor promoter studies with mixtures of PCDDs and halogenated biphenyls have shown additive, synergistic, and antagonistic effects. To analyse the interactions of TCDD and PCBs as tumor promoters in more detail, we established an in vitro assay, i.e., the enhancement (promotion) of malignant transformation of carcinogen-initiated C3H/M2 mouse fibroblasts after treatment with tumor promoters. The coplanar PCB 126, a potent Ah receptor agonist, and the diortho-substituted PCB153, to which no TEF value has been ascribed, are promoters of malignant transformation. A defined mixture of PCB126 and TCDD had an additive promoting effect, while PCB 153 antagonized the TCDD-mediated promotion. Thus, the TEF-approach may be insufficient to estimate the tumor-promoting activities of PCDDs, PCDFs, and PCBs in mammalian tissues in which diortho-substituted PCBs are greatly accumulated.
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PMID:Interactions between 2,3,7,8-TCDD and PCBs as tumor promoters: limitations of TEFs. 950 31

Why is there a small peak of germ cell tumours in the postnatal period and a major peak in young age, starting at puberty? And, paradoxically, small risk in old age, although spermatogenesis is a lifelong process? Why is this type of cancer more common in individuals with maldeveloped gonads, including undescended testis, gonadal dysgenesis and androgen insensitivity syndrome? Why has there, during the past 50 years, been a quite dramatic increase in testicular cancer in many developed countries? These are just a few of many questions concerning testicular cancer. However, the recent progress in research in the early stages of testicular cancer (carcinoma in situ testis (CIS)) allows us to begin to answer some of these questions. There is more and more evidence that the CIS cell is a gonocyte with stem cell potential, which explains why an adult man can develop a non-seminoma, which is a neoplastic caricature of embryonic growth. We consider the possibility that CIS cells may loose their stem cell potential with ageing. Along these lines, a seminoma is regarded a gonocytoma where the single gonocytes have little or no stem cell potential. The Sertoli and Leydig cells, which are activated postnatally and during and after puberty, may play a crucial role for both the development of the CIS gonocyte and progression of the neoplasm to invasiveness. The reported increase in testicular cancer is not the only sign that male reproductive health is at risk. There are reports that undescended testis and hypospadias have become more common. Also semen quality has deteriorated, at least in some countries. The epidemiological evidence suggests that environmental factors may play a role. Are the environmental hormone disrupters (e.g. DDT, PCB, nonylphenol, bisphenol A) to be blamed for the apparently synchronised deterioration in these aspects of male reproductive health?
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PMID:Germ cell cancer and disorders of spermatogenesis: an environmental connection? 952 57

The hepatic tumor-promoting activity of a mixture of polyhalogenated aromatic hydrocarbons (PHAHs) was studied in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The PHAH mixture contained 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 2,3,3',4,4', 5-hexachlorobiphenyl (PCB 156), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) and covered >90% of the total toxic equivalents (TEQ) present in Baltic herring. To determine possible interactive effects of di-ortho-substituted PCBs, the PHAH mixture was tested with (PHAH+) and without (PHAH-) PCB 153. Rats were initiated by a diethylnitrosamine injection (30 mg/kg body wt i.p.) 24 h after a partial 23 hepatectomy. Six weeks after initiation, the PHAH mixtures were administered once a week by subcutaneous injections for 20 weeks. Treatment with the PHAH mixtures caused liver enlargement and an increased activity of the hepatic cytochrome P4501A1/2 and P4502B1/2. All PHAH exposure groups exhibited an increased occurrence of hepatic foci positive for the placental form of glutathione-S-transferase. In the PHAH-group dosed 1 microgram TEQ/kg body wt/week, the volume fraction of the liver occupied by foci was significantly lower compared to the TEQ equivalent dosed TCDD group (3.8 vs 8.7%). The volume fraction was significantly increased in the groups treated with 0.5, 1, or 2 micrograms TEQ/kg body wt/week of the PHAH+ mixture (4.5, 5.2, and 6.6%, respectively) compared to the corn oil group (2.0%), but to a lower extent than expected on basis of the TEQ doses. Overall, the TEQ-based administered dose overestimated the observed tumor-promoting effects of this PHAH mixture. The applicability of the toxic equivalency factor concept, the role of differences in toxicokinetic properties and interactive effects of PCB 153 on hepatic deposition of the dioxin-like congeners are discussed.
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PMID:Induction of altered hepatic foci by a mixture of dioxin-like compounds with and without 2,2',4,4',5,5'-hexachlorobiphenyl in female Sprague-Dawley rats. 1010 Oct 96

We have analyzed the effect of polychlorinated biphenyls (PCB, Kanechlor-400) on 1-nitropyrene (1-NP) induced lung tumor. Male A/J mice (6 weeks old) were used for the experiment. A total of 2.5 mg/kg PCB was administered intraperitoneally (PCB group), a total of 0.38 mmol/kg 1-NP was administered intraperitoneally for 17 times (1-NP group), PCB was administered followed by i.p. injection of 1-NP (PCB + 1-NP group), and only vehicle was administered (control group). The lung lesions induced were examined 18 weeks after the final treatment with 1-NP or vehicle. In control group, no neoplastic lesion in the lung was induced. In PCB group, only one lesion with adenoma was induced. In 1-NP group, various kinds of lung neoplastic lesions including hyperplasia, adenoma and adenocarcinoma were induced. In PCB + 1-NP group, both the number and size of tumors induced were significantly more than those in 1-NP group. In addition, the number of adenocarcinoma formed was more in PCB + 1-NP group than in 1-NP group. Each lesion was microdissected to collect and analyze DNA of the targeted tissue. K-ras gene mutation was detected in part of adenoma lesions and all the carcinoma lesions. The mutation was found in either 1-NP or PCB + 1-NP group, but not in control and PCB group. The pattern of K-ras mutation was CAA to CGA in codon 61 or GGT to GAT in codon 12. There was no difference in the pattern of K-ras mutation despite of the pretreatment with PCB. Although the present data are from small sample size, it was suggested that PCB may promote (but not initiate) 1-NP induced lung tumorigenesis, and may not induce K-ras mutation directly in the experimental system.
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PMID:[Effect of PCBs on mouse lung tumorigenesis induced by 1-nitropyrene: a preliminary report]. 1039 79

The microsomal enzyme inducer (MEI), phenobarbital (PB), has been proposed to promote thyroid tumors by increasing the biotransformation and elimination of T(4), resulting in an increase in serum thyroid-stimulating hormone (TSH). In turn, TSH stimulates thyroid gland function, growth, and ultimately neoplasia. The dose-dependent effects of MEI on thyroid-follicular cell proliferation, a measure of thyroid gland growth, has not been reported. In the present study, it was hypothesized that MEIs that increase TSH would stimulate thyroid-follicular cell proliferation and the total number of thyroid-follicular cells. Male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), pregnenolone-16alpha-carbonitrile (PCN) (at 200, 400, 800, or 1600 ppm), 3-methylcholanthrene (3MC) (at 50, 100, 200, or 400 ppm), or Aroclor 1254 (PCB) (at 25, 50, 100, or 200 ppm) for 7 days. PB and PCN increased TSH 65% and 95%, respectively, whereas 3MC and PCB did not appreciably affect TSH. PB and PCN increased thyroid-follicular cell proliferation 625% and 1200%, respectively, whereas 3MC and PCB did not have a consistent or appreciable effect. The total number of thyroid-follicular cells was not significantly increased by MEI treatment. In conclusion, small increases in TSH by PB and PCN produced large increases in thyroid-follicular cell proliferation, which did not result in a comparable increase in the total number of thyroid-follicular cells. Furthermore, MEI that did not increase TSH did not consistently or appreciably increase thyroid-follicular cell proliferation or cell number.
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PMID:Effects of microsomal enzyme inducers on thyroid-follicular cell proliferation, hyperplasia, and hypertrophy. 1052 15

Many nongenotoxic hepatocarcinogens can induce cell proliferation, and inhibit apoptosis and gap-junctional-intercellular communication (GJIC). GJIC, the movement of small molecules (less than 1.2 kD) through membrane channels, is important in regulating cellular homeostasis and differentiation. The inhibition of hepatic GJIC can increase cell proliferation and possibly, inhibit apoptosis. In this study, the relationship between hepatic GJIC, proliferation, and apoptosis was examined in rats treated for 7 days with tumor-promoting doses of the nongenotoxic hepatocarcinogens phenobarbital (PB; 800 ppm), pregnenolone-16alpha-carbonitrile (PCN; 1000 ppm), and Aroclor 1254 (PCB; 100 ppm). In addition, 3-methylcholanthrene (3MC) was included as a negative control. PB, PCN, and PCB increased parenchymal-cell proliferation and inhibited hepatic apoptosis, while no alteration in these growth parameters was observed in 3MC-treated rats. GJIC, as measured by fluorescent-dye transfer through intact liver, was decreased nearly 50% by PB, PCN, and PCB, yet no effect on GJIC was observed in liver from 3MC-treated rats. These data indicate that compounds that inhibit GJIC in liver may be nongenotoxic hepatocarcinogens, which occurs simultaneously during increased cell proliferation and inhibited apoptosis.
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PMID:Inhibition of gap-junctional-intercellular communication in intact rat liver by nongenotoxic hepatocarcinogens. 1077 59

The hepatic tumor promoting activity of the planar 0-1 ortho ( approximately 9.7% w/w) and the nonplanar 2-4 ortho ( approximately 90.3% w/w) fraction of the commercial PCB mixture Aroclor 1260 was studied using a medium-term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. Fractionation was carried out on an activated charcoal column. The composition of the effluent from the column was tested by GC-ECD. The absence of planar compounds in the 2-4 ortho fraction was confirmed by GC-MS analysis. The dioxin-like toxic potency of the fractions was determined with the DR-CALUX assay. The animal experiment was started with the initiation procedure (diethylnitrosamine injection, 30 mg/kg body wt ip, 24 h after (2)/(3) hepatectomy), followed 6 weeks later by the promotion treatment, which consisted of a weekly subcutaneous injection during 20 weeks. Exposure groups (n = 10) received the following treatments (dose/kg body wt/week): Aroclor 1260 (10 mg), 0-1 ortho fraction (0.97 mg), 2-4 ortho fraction (1, 3, or 9 mg), a reconstituted 0-4 ortho fraction (9.97 mg), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153; 1 or 9 mg), 2,3,7,8-TCDD (1 microg; positive control) or corn oil (1 ml; vehicle control). One group did not receive a promotion treatment. All exposure groups exhibited a significantly increased volume fraction of the liver occupied by hepatic foci positive for the placental form of glutathione-S-transferase-p compared to the corn oil control, except for the groups treated with 0-1 ortho fraction and 1 mg PCB 153/kg body wt/week. Approximately 80% of the total tumor promoting capacity of the reconstituted 0-4 ortho fraction could be explained by the 2-4 ortho PCB fraction while the 0-1 ortho fraction had only a negligible contribution. These results suggest that the majority of the tumor promotion potential of PCB mixtures resides in the non-dioxin-like fraction, which is not taken into account in the toxic equivalency factor (TEF) approach for risk assessment of PCBs. This may result in an underestimation of the tumor promotion potential of environmental PCB mixtures.
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PMID:Contribution of planar (0-1 ortho) and nonplanar (2-4 ortho) fractions of Aroclor 1260 to the induction of altered hepatic foci in female Sprague-Dawley rats. 1113 48

PCBs are complete rodent carcinogens and their potent tumor promoting activity has been reported, but their tumor-initiating activity remains controversial. Macromolecular binding of PCB metabolites has been demonstrated in vitro, but this issue remains unclear in vivo. The purpose of this study was to determine the binding affinity of 4-chlorobiphenyl and 3,3',4,4'-tetrachlorobiphenyl to proteins and DNA in vivo. C57/BL6 female mice were treated intraperitoneally with hepatic enzyme inducers (phenobarbital and beta-naphthoflavone) and then with 14C-labelled polychlorinated biphenyls or benzo[a]pyrene. The short-term distribution of labeled compounds into liver, lungs and kidneys and into different sub-cellular fractions of these tissues was assessed and the DNA and proteins from the 700 x g pellet were further purified to assess covalent binding. All compounds were distributed in low amounts into the liver, kidneys and lungs, with the greatest accumulation in the liver, and the lowest in lungs. In all tissues, test compounds were mostly found in cytosols and organellar pellets (10,000 x g), and lower amounts were present in nuclear pellets (700 x g) and microsomes. In lungs and kidneys, only benzo[a]pyrene showed significant covalent binding to proteins. In the liver, protein binding indices were significant for all compounds (P<0.05), but no significant binding of the test compounds to DNA could be demonstrated with this approach. Our results suggest that at the 24 h time point, all compounds were activated to electrophilic intermediates prone to macromolecular binding. Hepatic proteins apparently act as a sink for PCB-derived electrophiles, thus preventing detectable levels of covalent binding to hepatic DNA or to proteins in less metabolically active tissues.
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PMID:Distribution and macromolecular binding of benzo[a]pyrene and two polychlorinated biphenyl congeners in female mice. 1156 92

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