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)

Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine. The fact that some drug-resistant cell lines have increased GSH levels, and that enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. We previously showed a selective enhancement by the cysteine "pro-drug," L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of tumor-bearing rats, whereas there is a paradoxic GSH depletion in tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model. We have examined the OTZ "activating" enzyme, 5-oxoprolinase, in these tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in tumor in response to OTZ. A limited number of human breast cancer samples show similar activity.
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PMID:Modulation of glutathione by a cysteine pro-drug enhances in vivo tumor response. 878 49

1,2-Dimethylhydrazine (DMH) is an organotropic colon carcinogen that undergoes metabolic activation to DNA-reactive metabolites. Twenty hours after parenteral treatment of AKR/J (colon tumor resistant) and SWR/J (susceptible) mice with DMH.2HCl (70 mg/kg), functional levels of Cyp1a1 and Cyp2e1 were examined by measuring O-deethylation of ethoxyresorufin (EROD) and hydroxylation of p-nitrophenol, respectively. In control animals, SWR/J mice exhibited higher hepatic EROD activity (1.4-fold) when compared with AKR/J mice. In carcinogen-treated animals, EROD activity was decreased 20-30% in both mouse lines. Hepatic p-nitrophenol hydroxylase activity, similar in control animals of both strains, was reduced comparably (45-50% of control) after DMH administration. In liver, a decrease in immunoreactive Cyp2e1 protein paralleled the decline in enzyme activity, whereas in the colon, no significant treatment-related differences were detected in either strain. In liver and colon cytosols, alcohol dehydrogenase activity was not significantly different in either mouse line, both in control and DMH-treated animals. Glutathione levels were elevated (1.7-fold) in livers of AKR/J mice after DMH administration. Total glutathione-S-transferase (GST) activity was significantly increased (1.8-fold) in the colons of SWR/J mice and in the livers (1.4-fold) of AKR/J mice. Furthermore, the GST isoform, GST-Yp, was reduced 40% in the SWR/J colon. These data demonstrate the importance of metabolic capacity as a factor in conferring differential tumor susceptibility in a murine cancer model to the indirect-acting colon carcinogen, DMH.
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PMID:A comparative study of hepatic and colonic metabolic enzymes in inbred mouse lines before and after treatment with the colon carcinogen, 1,2-dimethylhydrazine. 880 Oct 55

Glutathione has a variety of important physiological functions in cellular metabolism and defense, including protection from radicals, oxidative stress, and electrophilic compounds. On the basis of this interaction with both endogenous and synthetic substances, glutathione and the key enzyme for its conjugation, glutathione S-transferase, appear to be critical determinants in tumor cell resistance to several antineoplastic drugs, e.g. platinum analogs. In ten established head and neck cancer cell lines (UM-SCC 10A, 10B, 11B, 14A, 14B, 14C, and 22B, HLac79, 8029NA, and 8029DDP4) chemosensitivity to cisplatin, carboplatin, 5-fluorouracil, and bleomycin, as well as cellular glutathione content and activity of glutathione S-transferase were determined. The results revealed no correlation between the sensitivity of tumor cells to any of the drugs tested and the level of glutathione or the activity of glutathione S-transferase. However, the cisplatin-resistant subpopulation 8029DDP4 showed the highest glutathione level and marked cross-resistance to bleomycin. Glutathione depletion with buthionine sulfoximine led to moderately increased sensitivity towards cisplatin and carboplatin in all cell lines, but did not affect their response to 5-fluorouracil or bleomycin. These results suggest that the level of glutathione or the activity of glutathione S-transferase is not a suitable parameter for the assessment of chemosensitivity in head and neck squamous-cell carcinoma lines. However, response to platinum analogs is influenced by alterations of the initial intracellular glutathione concentration.
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PMID:Chemosensitivity of head and neck squamous carcinoma cell lines is not primarily correlated with glutathione level but is modified by glutathione depletion. 889 74

The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a "pump" that can extrude a wide range of anticancer drugs. Membrane-active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies including chemosensitizers have, however, been disappointing. (2) Non-PGP-mediated MDR: this phenotype is characterized by expression of other proteins in the plasma membrane which are also able to extrude anticancer drugs. (3) Changes in the intracellular distribution of drug: this mechanism has been demonstrated in several cell lines, most often in combination with PGP or non-PGP-mediated resistance. (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a multigene family of enzymes that conjugate glutathione to chemically reactive groups. Direct evidence for a causative role of GST in anthracycline resistance is missing. (5) Alterations in TOPO II (at-MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination, DNA transcription, and chromosome segregation. Low levels of expression or alterations in TOPO II are associated in vitro with resistance. (6) Increased DNA repair: in several cell lines, an increase in the efficacy of DNA repair has been associated with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.
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PMID:Cellular resistance to anthracyclines. 891 38

Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of xenobiotics and are divided into four subclasses. Alpha, Mu, Pi and Theta. Most human gastrointestinal tumors contain increased amounts of GST Pi. In order to compare data on the expression of GSTs obtained by biochemical as well as immunohistochemical methods, we characterized the presence of GST Alpha and Pi by Western blot analysis and immunohistochemistry in 22 samples of human gastric carcinoma and adjacent non-neoplastic mucosa. Biochemical analyses revealed the presence of GST Alpha and Pi in 95% and 91% of normal tissues and in 82% and 100% of tumor specimens, respectively. Immunohistochemically all cases of normal gastric tissue stained for both GST Alpha and Pi, whereas immunostaining for GST Alpha and Pi was seen in 36% and 100% of the gastric tumor specimens, respectively. No statistically significant correlation however was observed between biochemical and immunohistochemical determination of GST Alpha and Pi both in normal as well as in malignant tissue. The absence of a statistically significant correlation between biochemical and immunohistochemical determination of GST Alpha and Pi implies that a high degree of caution must be taken in interpretating data derived solely from biochemical or immunohistochemical assays.
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PMID:Glutathione S-transferases in gastric carcinomas and in adjacent normal gastric epithelium: immunohistochemical and biochemical analyses. 904 47

Glutathione, glutathione S-transferases alpha and pi, and aldehyde dehydrogenase are associated with resistance to carboplatin and/or cyclophosphamide in cell lines. Therefore, we examined whether the expression of these factors in ovarian cancer tissue specimens is associated with resistance of the patients to combination chemotherapy with cyclophosphamide/carboplatin. Ovarian cancer tissue specimens were taken intraoperatively from 139 patients and frozen in liquid nitrogen, and the contents of glutathione S-transferases alpha and pi, total glutathione, and aldehyde dehydrogenase activity were determined. No association between the levels of glutathione S-transferases alpha and pi or aldehyde dehydrogenase activity in tumor tissue and the survival time was observed in patients with primary ovarian cancer. Significantly higher levels of aldehyde dehydrogenase were observed in FIGO stage I and II compared to FIGO stage III and IV tumors (P = 0.019, Wilcoxon test, two sided). The median survival time was significantly longer in patients with primary ovarian cancer with a tumor glutathione content of <4.9 microg/mg protein compared to patients with a tumor glutathione content of > or =4.9 microg/mg protein (P = 0.047). However, glutathione was not an independent prognostic factor, but was significantly associated with FIGO stage resulting in higher levels in FIGO stage III and IV tumors than in FIGO stage I and II tumors (P = 0.0094, Wilcoxon test, two sided). In conclusion the glutathione content was associated with progression of ovarian carcinomas but neither glutathione nor glutathione S-transferases alpha and pi or aldehyde dehydrogenase were independent factors of resistance to cyclophosphamide/carboplatin.
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PMID:Glutathione, glutathione S-transferase alpha and pi, and aldehyde dehydrogenase content in relationship to drug resistance in ovarian cancer. 910 91

Glutathione S-transferases (GSTs) of female A/J mouse lung have been purified and characterized for their (a) structural interrelationships, (b) substrate specificities toward the ultimate carcinogenic metabolite of benzo(a)pyrene (BP), (+)-anti-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE], and (c) induction by three naturally occurring organosulfides (OSCs)-from garlic [diallyl sulfide (DAS), diallyl trisulfide (DATS) and dipropyl sulfide (DPS)], which significantly differ in their efficacy against BP-induced lung cancer in mice. The GST activity in the lung was due to two alpha class (pI 9.4 and 6.0), two mu class (pI 8.7 and 8.6), and one pi class (pI 8.9) isoenzyme. The GST isoenzyme profile of the lung was different from that of the A/J mouse forestomach, which also is a target organ for BP-induced cancer in mice. Noticeably, an alpha class heterodimeric isoenzyme (pI 9.5) present in the forestomach of A/J mouse, which is exceptionally efficient in the glutathione (GSH) conjugation of (+)-anti-BPDE [X. Hu, S.K. Srivastava, H. Xia, Y. C. Awasthi, and S. V. Singh (1996) J. Biol. Chem. 271, 32684-32688], could not be detected in the lung. The specific activities of the lung GSTs in the GSH conjugation of (+)-anti-BPDE were in the order of GST 8.9 > GST 8.7 > GST 9.4 > GST 6.0. While DPS treatment did not increase the levels of any pulmonary GST isoenzyme, the expression of pi class GST 8.9 was significantly increased in response to both DAS and DATS administrations. Interestingly, DATS, an OSC which lacks activity against BP-induced lung cancer in mice, was a relatively more potent inducer of pi class GST isoenzyme than DAS, which is a potent inhibitor of BP-induced lung tumorigenesis. The results of the present study suggest that a mechanism(s) other than GST induction is likely to be responsible for the differential effects of DAS and DATS on BP-induced lung cancer in mice. Our results also suggest that relatively lower efficacies of the OSCs against BP-induced lung cancer than against forestomach neoplasia may be attributed to (a) a lack of expression in the lung of an isoenzyme corresponding to forestomach GST 9.5 and (b) a comparatively lower level of induction of pi type GST in the lung than in the forestomach by these OSCs.
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PMID:Glutathione S-transferases of female A/J mouse lung and their induction by anticarcinogenic organosulfides from garlic. 914 32

There are several major groups of multidrug resistance mechanisms. 1) The multidrug resistant phenotype. 2) Glutathione S-transferences (GST) and detoxification mechanisms. 3) Topoisomerase I and II. 4) DNA repair. 5) Drug activation by cytochrome P450 (P450). In this article the biochemical functions of GST and P450 are described to show how individual enzymes contribute to resistance to carcinogens and anti-tumor drugs. Cancer cell lines indicated resistant to anti-cancer drugs, such as mitomycin C, doxorubicin, tamoxifen, cyclophosphamide and their derivatives, by a high activity of GST and a low activity of P450 in general. However, the mechanism of change of these enzyme activities is complicated and different in each drug. We show the study on the mechanism of multidrug resistance using cancer cell lines.
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PMID:[Multidrug-resistance by induction of inactivation for anti-cancer drugs]. 915 50

Glutathione (GSH) plays an essential role in the metabolism of melanoma. As changes in intracellular GSH content can modify the processes of cell proliferation and detoxification, this could determine the therapeutic response to some cancer treatment strategies. The purpose of this study was to test the effects of treatment with interleukin-2 (IL-2), alone and in combination with cyclophosphamide (CY), on survival of mice bearing B16 melanoma liver metastases, and to determine the influence of these therapeutic agents on the GSH metabolism of B16 cells. In the in vivo test system, B16 melanoma liver metastases were induced in C57BL/6 mice which were subsequently treated with IL-2, CY and CY plus IL-2. Survival time was used to determine the response to treatment. In the in vitro system, we evaluated the effects of IL-2, acrolein (an active metabolite of CY responsible for GSH depletion) and acrolein plus IL-2 on GSH levels and proliferation of B16 melanoma cells. Results indicated that, in vivo, all treatments increased mouse survival times with respect to control mice. However, the addition of IL-2 to CY therapy decreased survival time compared with treatment with CY alone. In vitro, whereas acrolein produced a GSH depletion and inhibited B16 cell proliferation, IL-2 increased GSH content and cell proliferation rate compared with untreated cells. Moreover, addition of IL-2 to cells preincubated with acrolein increased GSH levels and proliferation with respect to acrolein alone. In summary, the data suggest that GSH plays a critical role in the growth-promoting effects of IL-2 on B16F10 melanoma cells and in the antagonistic effect of IL-2 on CY inhibitory activity on these tumor cells.
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PMID:Interleukin-2 increases intracellular glutathione levels and reverses the growth inhibiting effects of cyclophosphamide on B16 melanoma cells. 917 32

Glutathione S-transferases (GST, E.C.2.5.1.18) comprise a family of detoxification enzymes. Elevated levels of specific GST isozymes in tumor cells are thought responsible for resistance to chemotherapeutics, which renders selective GST inhibitors potentially useful pharmaceutical agents. We discuss the development of a structure activity model that rationalizes the isozyme selectivity observed in a series of 12 glutathione (GSH) analogues. Enzymatic activity data was determined for human P1-1, A1-1, and M2-2 isozymes, and these data were then considered in light of structural features of these three GST proteins. A survey of all GST structures in the PDB revealed that GSH binds to these proteins in a single "bioactive" conformation. To focus on differences between binding sites, we exploited our finding of a common GSH conformation and aligned the GST x-ray structures using bound ligands rather than the backbones of the different proteins. Once aligned, binding site lipophilicity and electrostatic potentials were computed, visualized, and compared. Docking and energy minimization exercises provided additional refinements to a model of selectivity developed initially by visual analysis. Our results suggest that binding site shape and lipophilic character are key determinants of GST isozyme selectivity for close GSH analogues.
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PMID:Ligand-based protein alignment and isozyme specificity of glutathione S-transferase inhibitors. 918 38

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