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)

This study examined the level of glutathione (GSH)--a tripeptide that may have an important role in detoxification of carcinogens--in the hamster buccal pouch mucosa (HBPM) by a 12-week regimen of tri-weekly topical application of 7,12-dimethylbenz[a]anthracene (DMBA) in mineral oil. GSH was quantified periodically and shown to be doubled in carcinogen-treated vs. control pouch mucosa. In the tumors that developed, the level of GSH was three times that of the controls. Previous studies showed that gamma-glutamyl transpeptidase (GGT), one of the enzymes that may be responsible for the detoxification of carcinogens, was increased in the hamster mucosa pre-neoplastic foci, but decreased with the formation of overt neoplasia. GGT and GSH are intimately related, since GGT is the only enzyme that can cleave the intact GSH molecule. The increase in both GSH and GGT levels may be responsible for the increased resistance of the pre-neoplastic pouch epithelium to the toxic effects of the carcinogen.
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PMID:Alteration in glutathione level during carcinogenesis of hamster buccal pouch mucosa. 167 9

Cytotoxic effects of vitamin K3 were evaluated utilizing the P388/S, L1210, EAT, S-180 and a multidrug-resistant variant of the P388 leukemia cells (P388/ADR). Antitumorigenic potential of vitamin K3 was assessed by MTT and DNA and RNA biosynthesis inhibition assay. A dose-dependent inhibition of P388/S and P388/ADR cell survival and [3H]thymidine and [3H]uridine incorporation (as a function of DNA and RNA biosynthesis) was observed in tumor cell types exposed to vitamin K3 concentrations ranging from 1 to 100 microM. One hundred mg/kg vitamin K3 caused a 32 and 52% increase in life span of the sensitive and resistant P388 leukemia tumor-bearing mice. Induction of DNA strand breaks at 100 microM vitamin K3 was greater in P388/S than in P388/ADR cells. In vitro treatment with vitamin K3 (100 microM) reduced the intracellular levels of GSH by 40, 47, 6, 15 and 14% in P388/S, P388/ADR, EAT, S-180 and L1210 tumor cells, respectively. In vivo treatment with 100 mg/kg vitamin K3 reduced the GSH content by 18 and 38% and increased the activity of the enzyme GSH-S-transferase and gamma-glutamyl transpeptidase. Effects of free radical scavengers and of compounds that modulate the GSH metabolism on the cytotoxicity of vitamin K3 were also investigated. Results indicate that vitamin K3 interacts with the tumor cell thiol pools while eliciting its antitumor effects and suggest the utility of vitamin K3 in dealing with the growing problem of multidrug resistance.
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PMID:Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells. 168 89

Squamous cell carcinomas (SCC) of the mouse skin were produced by three different protocols of chemical carcinogenesis, i.e., complete carcinogenesis with 7,12-dimethylbenz(a)anthracene (DMBA) two-stage carcinogenesis with DMBA as initiator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter and three stage carcinogenesis with DMBA, TPA and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as third-stage agent or progressor. Tumors were sequentially studied at weeks 38-52 of treatment. Although no significant differences in the rate of appearance of gamma-glutamyl transpeptidase (GGT) could be seen, a larger number of SCC produced by complete carcinogenesis protocols were GGT-negative. This coincided with the higher grade of malignancy of these tumors as evaluated by histopathology. In general terms high-grade tumors were seen more frequently in the complete carcinogenesis experiment than in the other two protocols. SCC produced by complete carcinogenesis also exhibited a markedly higher DNA index than the SCC from the other experimental groups. All three protocols were very effective in producing late metastasizing tumors, and no significant differences could be established in the incidence of spontaneous lung metastasis. This shows that, contrary to general knowledge, if adequately observed for more than 40 weeks, SCC of the murine skin is able to metastasize in the lung in approximately 30% of cases. Nevertheless, complete carcinogenesis-induced SCC were usually of higher histological grade, a proportion of these were GGT-negative and produced more multiple or diffuse metastases than the tumors induced by the multistage protocols.
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PMID:Metastatic potential of mouse skin carcinomas produced by different protocols of chemical carcinogenesis. 168 75

The premalignant evolution of chemically induced mouse skin papillomas is characterized by dysplastic changes, aneuploidy, induction of gamma-glutamyl transpeptidase (GGT), and changes in the expression of keratins, especially differentiation-associated K1. This keratin, which is expressed in normal epidermis and early papillomas, is no longer present in more advanced dysplastic and aneuploid papillomas and in fully invasive carcinomas. More recently, it has been shown that K13, a keratin normally present in internal epithelia but not in epidermis, is aberrantly expressed in epidermal tumors. In the present study, the timing of expression of K13 and its correlation with other markers of premalignant evolution were investigated. Papillomas were induced by SENCAR mice by a single initiating dose of 20 nmol of 7,12-dimethylbenz[a]-anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 micrograms twice a week). Tumors were randomly harvested at 10, 20 and 35 weeks of promotion. K13 and K1 expression in papillomas was studied using immunoblotting and immunostaining of consecutive sections, as previously described. As expected from previous studies, the distribution of K1 in papillomas collected at 10 weeks of promotion was restricted to differentiated cells and was uniform throughout the section of the papilloma. Conversely, K13 was expressed only as small foci in 10 out of 21 papillomas (48%). Papillomas of 20 weeks were also positive for K1. Staining for K13 was positive in these papillomas with the exception of only one that was essentially negative, presenting only one small positive focus. Some of the papillomas collected at week 35 were negative for K1, but immunostaining with K13 showed uniform staining of suprabasal cells in all the papillomas studied. In all cases, immunohistochemical results were confirmed by immunoblotting with proteins extracted from 7 microns sections from each paraffin block. These results indicate that keratins K1 and K13 are coexpressed in most papillomas from 10 to 35 weeks of promotion. However, analysis of adjacent sections showed that K13 positive areas are topographically located in the K1 negative areas of the papillomas, suggesting a shift in the differentiation program from epidermal to mucosal types of keratinization. Based on these and previous studies from our laboratory, we conclude that K13 is an early marker of papillomas progression, which occurs before gross chromosomal abnormalities are present in the stem line of the tumors, and precedes dysplastic changes and the onset of GGT expression, and is probably concomitant at the individual cell level with loss of K1.
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PMID:Early expression of type I K13 keratin in the progression of mouse skin papillomas. 169 81

The pattern of gene expression in fetal hepatocytes transformed in culture with a hepatocarcinogen (FRL cells) is studied with respect to a range of markers which are either developmentally regulated and/or shown to be expressed at high levels in hepatoma cells. The relative abundance of the respective mRNAs is determined and immunocytochemistry is used to detect the respective proteins in cultured cells. When compared with its normal counterpart, FRL cells retain the expression of transferrin, alpha 1-acid glycoprotein, gamma-glutamyltranspeptidase, and tyrosine aminotransferase at near normal levels, while expression of the liver-specific isoenzymes of pyruvate kinase (L form) and aldolase (B form) is reduced. The cell lines are different in that they fail to express albumin, alpha-fetoprotein, thiostatin and alpha 2-macroglobulin, and they express high levels of M2-pyruvate kinase and aldolase A, markers often found in abundance in hepatoma cells. Therefore transformation has resulted in different effects on different genes. Furthermore, it is of interest to find that the cells coexpress both forms of the pyruvate kinase isoenzymes which does not occur in the normal developing hepatocyte. These results indicate that it is possible to use this model to study changes which accompany transformation of fetal rat hepatocytes. The resulting cell lines have a stable phenotype and retain the changes which result from transformation even after extended passaging. This facilitates comparisons between the precursor cell and the tumor cell, both of which can be maintained under controlled conditions which exist in culture.
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PMID:Gene expression in clonally derived cell lines produced by in vitro transformation of rat fetal hepatocytes: isolation of cell lines which retain liver-specific markers. 170 49

The benzofurane derivative benzbromarone (BBR) previously has led to liver tumor formation after long-term treatment of rats, but no indications of genotoxicity were detected. The present studies were designed to elucidate the mechanism(s) possibly involved in liver tumor formation by BBR. Female Wistar rats were used. Phenobarbital (PB) served as a positive control. (1) Short-term treatment (7 days) with daily doses of 2 to 100 mg/kg BBR led to adaptive responses in the liver, i.e., growth (increases in DNA, RNA, and protein) and induction of monooxygenases. These changes were also observed after feeding BBR for 8, 33, 77, and 102 weeks at doses of 2, 10, and 50 mg/kg/day but tended to weaken with time. Similar effects were obtained with PB fed at 2, 10, or 50 mg/kg/day. However, unlike PB, BBR did not enhance the expression of cytochrome P450-PB as demonstrated by immunostaining of histological liver sections. (2) BBR feeding for 102 weeks, but not for 77 weeks, produced some neoplastic liver nodules and at 50 mg/kg produced one hepatocellular carcinoma (HCC). Thus, BBR was tumorigenic in the present study, but was clearly weaker than PB which had induced liver nodules and HCCs at 77 weeks and even more markedly at 102 weeks. (3) To check for tumor-initiating activity 100 mg/kg BBR was given 14 hr after a two-thirds hepatectomy followed by promotion with PB (50 mg/kg) for 15 weeks. No phenotypically altered liver foci were detected. (4) To test for tumor-promoting activity rats received a single dose of N-nitrosomorpholine (250 mg/kg), and subsequently BBR or PB at doses of 2, 10, and 50 mg/kg/day. While PB markedly enhanced the development of neoplastic nodules and HCCs, BBR had only a weak enhancing effect on the induction of HCC, which was not dose related. gamma-glutamyl transpeptidase-positive foci dramatically increased in PB-treated animals, in contrast they showed no response after 2 and 10 mg/kg BBR and even decreased after 50 mg/kg BBR. (5) With PB changes in liver growth, monooxygenase activity, foci expansion, and tumor promotion all correlating with tumorigenesis in a quantitative manner, apparent no-observed-effect-levels are somewhat below 2 mg/kg (or 10 mg/kg for liver enlargement). (6) These studies suggest that BBR belongs to a group of nongenotoxic, growth-stimulating drugs with tumorigenic potential in rat liver. Its effects on the liver are different from those of PB, but seemed to resemble those of peroxisome proliferators, a hypothesis studied in the subsequent papers.
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PMID:Toxicological studies on a benzofurane derivative. I. A comparative study with phenobarbital on rat liver. 170 30

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
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PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

Oval cells may function as facultative liver stem cells and tumor progenitors in liver carcinogenesis. The authors determined whether oval cells proliferate and if small hepatocytes might be generated from epithelial cell progenitors in noncarcinogenic liver injury. The authors found that oval cells similar to those detected in early carcinogenesis proliferate in response to D-galactosamine (GaIN). Oval cells expressed gamma-glutamyl transpeptidase activity, bile duct-type cytokeratins and peanut agglutinin binding. Two unusual types of hepatocytes also appeared after injury: small hepatocytes (less than or equal to 16 microns in diameter) and hepatocytes lining atypical ductlike structures. In situ hybridization studies showed that the fetal form of alphafetoprotein mRNA was expressed by many oval cells, some bile duct cells, and occasional hepatocytes. By following the fate of epithelial cells labeled early after GaIN administration, the authors conclude that duct cells can generate both oval cells and small hepatocytes in response to GaIN.
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PMID:Oval cell proliferation and the origin of small hepatocytes in liver injury induced by D-galactosamine. 171 45

The cellular origin of estrogen-induced kidney tumors in male Syrian hamsters has been repeatedly the subject of controversy. Several authors have proposed that the tumors arise from proximal tubules, from a combination of tubular and interstitial stromal cells, or solely from interstitial cells. Because of the model character of this tumor for hormone-associated cancer, it was further investigated in this study with respect to morphology, enzyme and intermediate filament pattern, the expression of alpha-smooth muscle actin and the extracellular matrix proteins fibronectin and tenascin. These analyses were carried out with early and late tumors as well as metastases to determine possible changes in expression of biochemical parameters during the development and progression of this neoplasm. The enzyme histochemical and intermediate filament patterns were usually the same as those described previously for proliferative foci and early tumors, i.e. highly elevated activities of glucose-6-phosphate dehydrogenase, adenylate cyclase and alkaline phosphatase, a lack of glucose-6-phosphatase and gamma-glutamyltransferase and coexpression of vimentin and desmin, alpha-smooth muscle actin could not be detected in early lesions. In five of 24 advanced tumors inclusions of kidney tubules were found which showed various degrees of alteration in their morphology and enzyme histochemical pattern, but were often directly connected with tubular segments of normal appearance outside the tumor. Like the normal tubules, the enclosed tubular segments were strongly positive for cytokeratin but never expressed vimentin or desmin. Among the 24 tumors studied, two contained cysts which expressed cytokeratin and sometimes also vimentin but not desmin. The enzyme histochemistry of the cells lining the cysts was similar to that of the surrounding tumor mass, except adenylate cyclase was lacking and alkaline phosphatase was not uniformly distributed. In tumors containing cytokeratin-positive cysts, there often were cytokeratin-positive, vimentin-negative and desmin-negative tumor formations in close contact to these cysts. With the exception of cyst formation, the pattern of metastases were identical to that of the primary tumors. All large tumors and the main component of the metastases expressed vimentin, desmin and fibronectin. Mesothelia surrounding metastatic tumor complexes were positive for vimentin, desmin, alpha-smooth muscle actin, fibronectin, cytokeratin and tenascin. It was concluded from these and previous observations on early stages of tumor development that the estrogen-induced hamster kidney tumor originates from mesenchymal interstitial cells (probably pericytes) which may rarely acquire an epithelial phenotype by metaplastic transformation during tumor progression.
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PMID:Changes in the cellular phenotype and extracellular matrix during progression of estrogen-induced mesenchymal kidney tumors in Syrian hamsters. 171 81

To examine the influence of retinol acetate (retinol, known as an inhibitor of tumor promotion) on 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB)-induced hepatocarcinogenesis, rats were fed with a diet containing 0.06% 3'MeDAB for 4 or 7 weeks and then with a normal diet for 21 or 18 weeks. Rats were given retinol (0, 6.25, 12.5 and 25.0 mg/rat, dissolved in DMSO) i.p. every 5 days from the 10th week to the 20th week. As a control, rats were fed a basal diet and given retinol at the same doses as mentioned above. At the 25th week, the incidence of hepatoma (hepatocellular carcinoma and cholangiocarcinoma) of each group was checked. In rats fed diet containing 3'MeDAB for 7 weeks, significant increases in the incidence of hepatoma were seen in retinol-treated groups at various doses. In rats fed 3'MeDAB diet for 4 weeks, all three doses also moderately, though not significantly, increased the incidence of hepatoma. No liver tumor was found in rats fed normal diet followed by treatment with retinol at any dose. Except for slight but detectable elevation of cellular retinoic acid binding protein levels in tumor tissues obtained from rats treated with retinol, no obvious differences in cellular retinol binding protein and gamma-glutamyl transpeptidase in the tumor tissues were observed between retinol-treated and untreated rats. Phytohemagglutinin-induced lymphocyte blastogenesis of the tumor-bearing rats with or without retinol treatment showed approximately 50% inhibition compared with that of rats fed normal diet without retinol treatment. These results indicated that the administration of retinol in the early stages of hepatocarcinogenesis enhanced the tumor induction, possibly due to the fixation of malignant transformation of the cells.
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PMID:The facilitated effect of retinol on rat hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene. 172 Oct 9


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