Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine leukemia L1210 cells rendered deficient in glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) by Se deprivation (L.Se(-) cells) were found to be more sensitive to tert-butyl hydroperoxide (t-BuOOH) cytotoxicity than Se-replete controls (L.Se(+) cells). Human K562 cells, which express PHGPX, but not GPX, were also more sensitive to t-BuOOH in the Se-deficient (K.Se(-)) than Se-satisfied (K.Se(+)) condition. In examining the metabolic basis for selenoperoxidase-dependent resistance, we found that glucose-replete Se(-) cells reduce t-BuOOH to t-butanol far more slowly than Se(+) cells, the ratio of the first-order rate constants approximating that of the GPX activities (L1210 cells) or PHGPX activities (K562 cells). Monitoring peroxide-induced changes in GSH and GSSG gave consistent results; e.g., glucose-depleted L.Se(+) cells exhibited a first order loss of GSH that was substantially faster than that of glucose-depleted L.Se(-) cells. Under the conditions used, peroxide-induced conversion of GSH to GSSG could be stoichiometrically reversed by resupplying D-glucose, indicating that no significant lysis or GSSG efflux and/or interchange had taken place. The apparent first-order rate constant for GSH decay increased progressively for L1210 cells expressing a range of GPX activities from approximately 5% to 100%, demonstrating that peroxide detoxification is strictly dependent on enzyme content. The initial rate of 14CO2 release from D-[1-14C]glucose supplied in the medium was much greater for L.Se(+) or K.Se(+) cells than for their respective Se(-) counterparts, consistent with greater hexose monophosphate shunt activity in the former. These results highlight the importance of selenoperoxidase action in the glutathione cycle as a means by which tumor cells cope with hydroperoxide stress.
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PMID:Selenoperoxidase-dependent glutathione cycle activity in peroxide-challenged leukemia cells. 777 66

The "in vivo" effect of cycloplatam on DNA synthesis in leukemia P388/o (parent strain), P388/c (cycloplatam-resistant strain) and in some organs of tumour-bearing mice, such as spleen, kidney, gastrointestinal mucosa (GI mucosa) and bone marrow, has been studied. Cycloplatam induced a deep and stable inhibition of DNA synthesis in leukemia cells and kidney. DNA synthesis in normal dividing cells (GI mucosa, bone marrow, spleen) was shown to recover more rapidly than in leukemia cells and kidney after cycloplatam treatment. The GSH level was increased tenfold in leukemia P388/c cells in comparison with P388/o. The glutathione peroxidase and glutathione reductase activities were increased twofold in the resistant strain in comparison with the parent strain, while the activity of glutathione-S-transferase showed a 1.5-fold increase. Administration of cycloplatam to tumour-bearing mice caused a marked increase of the GSH level in the both leukemia strains. Alterations in GSH-dependent enzymes following cycloplatam therapy were expressed in a lesser degree. These data indicate that GSH and GSH-dependent enzymes may play an important role in the resistance of P388 leukemia cells to cycloplatam.
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PMID:[Biochemical mechanisms of resistance to a new antineoplastic agent amin(cyclopeptidylamin)-S-(-)-malatoplatinum (II) (cycloplatam)]. 777 82

The intracellular glutathione (GSH) content was measured in 73 patients with leukemia and compared with controls. GSH content was between 1.16 and 5.55 mumol/g protein (mean 2.96 +/- 0.86) in the study group and between 0.5 and 1.48 mumol/g protein (mean 1.31 +/- 0.27) in the control group, statistically significant difference (p = 0.0000). There was no significant difference between acute and chronic leukemias, lymphoid and myeloid leukemias and, more importantly, newly diagnosed and relapsed patients. GSH content did not change significantly with clinical and hematologic parameters such as age, sex, and initial hematologic findings. In addition, variable changes were detected over 24 h in 9 patients. It can be concluded that GSH content in leukemic cells was higher than in controls and showed a wide range. The absence of a relationship between GSH content and clinical and laboratory parameters suggested that GSH is not the sole determinant of response to cytotoxic drugs. GSH variation over a 24-hour period may be important in the timing and success of chemotherapy for leukemias.
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PMID:Intracellular glutathione content in leukemias. 785 69

Murine L1210 and human HL-60 leukemia cells grown for 5-7 days in medium containing 1% serum without selenium supplementation [Se(-) cells] were severely depressed in selenoperoxidase (SePX) activity relative to selenium-supplemented controls [Se(+) cells]. Catalase (CAT) activity in Se(-) cells was unaffected up to this point, but thereafter began to increase. Two manifestations of this increase have been differentiated for both cell lines: (a) short-term induction of CAT (up to approx. twofold) after 2-3 weeks, followed by (b) long-term selection for cells that irreversibly express much higher levels of CAT, e.g., > 100 times (L1210) and > 10 times (HL-60) the levels observed in Se(+) controls after approximately 20 weeks. Although superoxide dismutase, glutathione S-transferase, and glucose-6-P dehydrogenase activities were unchanged in Se(-) cells, GSH levels were elevated by 50-100%; like short-term CAT elevation, this could be reversed by supplying Se. Short-term Se(-) cells were more sensitive to H2O2-induced killing than Se(+) cells, evidently because SePX activity was important for peroxide detoxification. However, long-term Se(-) cells were markedly more resistant to H2O2 than Se(+) counterparts, consistent with the much higher levels of CAT in the former. Southern blot analysis revealed that the copy number of CAT DNA in a clone of long-term Se(-) L1210 cells was four- to fivefold greater than that in an Se(+) clone. Northern blot analysis of RNA from the same Se(-) clone showed a CAT mRNA level that was at least 40 times higher than that of the Se(+) control. Similar trends were observed for HL-60 cells. These results suggest that elevated CAT during long-term Se deprivation is a reflection of amplification and greater transcription of the CAT gene.
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PMID:Amplification and hyperexpression of the catalase gene in selenoperoxidase-deficient leukemia cells. 787 6

Viral vectors and protein carriers utilizing asialoglycoprotein receptor (ASGR)-mediated endocytosis are being developed to transfer genes for the correction of bilirubin-UDP-glucuronosyltransferase (bilirubin-UGT) deficiency. Ex vivo evaluation of these gene transfer vectors would be facilitated by a cell system that lacks bilirubin-UGT, but expresses differentiated liver functions, including ASGR. We immortalized primary Gunn rat hepatocytes by transduction with a recombinant Moloney murine leukemia virus expressing a thermolabile mutant SV40 large T antigen (tsA58). At 33 degrees C, the immortalized hepatocyte clones expressed SV40 large T antigen, synthesized DNA, and doubled in number every 2 to 3 days. At this temperature, differentiated hepatocyte markers, e.g., albumin, ASGR, and androsterone-UGT, were expressed at 5% to 10% of the levels found in primary hepatocytes maintained in culture for 24 hours. Glutathione-S-transferase Yp (GST-Yp), an oncofetal protein, was expressed in these cells at 33 degrees C, but was undetectable in primary hepatocytes. In contrast, when the cells were cultured at 39 degrees C or 37 degrees C, the large T antigen was degraded, DNA synthesis and cell growth stopped, and morphologic characteristics of differentiated hepatocytes were observed. The expression of albumin, ASGR, and androsterone-UGT, and their corresponding mRNAs, increased to 25% to 40% of the level in primary hepatocytes, whereas GST-Yp expression decreased. Functionality of ASGR was demonstrated by internalization of Texas red-labeled asialoorosomucoid, and binding and degradation of 125I-asialoorosomucoid. After liposome-mediated transfer of a plasmid containing the coding region of human bilirubin-UGT1, driven by the SV40 large T promoter, active human bilirubin-UGT1 was expressed in these cells. The immortalized cells were not tumorigenic after transplantation into severe combined immunodeficiency mice. These conditionally immortalized cells will be useful for ex vivo evaluation of bilirubin-UGT gene transfer vectors.
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PMID:Conditional immortalization of Gunn rat hepatocytes: an ex vivo model for evaluating methods for bilirubin-UDP-glucuronosyltransferase gene transfer. 787 82

Adult T cell leukemia-derived factor (ADF) is a human homologue of thioredoxin (TRX) with many biological functions and is induced by various stimuli and stress. In the central nervous system (CNS), expression of ADF/TRX occurs in glial cells during ischemia and reperfusion. We showed that ADF/TRX was actively released from U251 astrocytoma cells upon exposure to a low concentration of H2O2. The addition of conditioned medium from H2O2-stimulated U251 cells or recombinant ADF (rADF) to the culture medium promoted the survival of neurons from embryonic mouse cortex and striatum, but the addition of mutant ADF (mADF), which has no reducing activity, did not. In addition to rADF, incubation with two other thiol compounds, 2-mercaptoethanol (2-ME) and N-acetyl-L-cysteine (NAC), also increased the neuronal cell survival rate. In contrast, L-buthionine-(S,R)-sulfoximine (BSO), which inhibited the synthesis of glutathione (GSH), decreased the neuronal cell survival rate. Intracellular GSH was increased by incubation with rADF for 24 h, as it is with 2-ME and NAC. Redox active molecules such as thiol compounds may be survival factors for central neurons in vitro, and this capacity may be supplied by endogenous molecules, such as ADF/TRX and glutathione, under certain pathologic conditions in vivo.
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PMID:Neuroprotection by glial cells through adult T cell leukemia-derived factor/human thioredoxin (ADF/TRX). 795 44

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance has been mostly studied in vitro. In an attempt to better understand BCNU resistance in the in vivo situation, we compared the principal drug-metabolizing enzyme systems in two L1210 leukemia lines, one sensitive and one resistant to BCNU (L1210/BCNU), passaged in vivo in mice. The following enzymes were assayed by immunoblotting: cytochromes P-450 (1A1/1A2, 2B1/2B2, 2C8-10, 2E1, 3A), epoxide hydrolase (EH) and glutathione S-transferase (GST-alpha, -mu and -pi). The following enzymes and cofactors were assayed fluorometrically or spectrophotometrically: 1-chloro-2-4 dinitrobenzene-GST (CDNB-GST), total glutathione (GSH), UDP-glucuronosyltransferase, beta-glucuronidase, sulfatase and sulfotransferase. Results showed that cytochrome P-450 1A1/1A2 was the only isoenzyme detected in both L1210 and L1210/BCNU. CDNB-GST activity was significantly higher in L1210/BCNU compared with L1210. The isoenzyme GST-alpha was more abundant in L1210/BCNU compared with L1210, whereas GST-pi was expressed less in the BCNU-resistant leukemia line. GST-mu was not detected in either L1210 leukemia lines. GSH levels were similar in the two L1210 lines. No significant difference was observed between the two leukemia lines for the conjugative enzymes UDP-glucuronosyltransferase and sulfotransferase, whereas their corresponding hydrolytic enzymes beta-glucuronidase and sulfatase were about two-fold lower in the BCNU-resistant leukemia line. Epoxide hydrolase was 1.3-fold higher in L1210/BCNU compared with L1210 and this level was about three-fold higher than in mouse liver. In conclusion, these studies showed the presence of cytochrome P-450 1A1/1A2 in the two L1210 leukemia lines studied, and indicated noteworthy differences between the two leukemia lines for many enzyme systems such as GST, beta-glucuronidase, sulfatase and epoxide hydrolase. These data are of importance to better understand the mechanisms of drug resistance to nitrosoureas in vivo.
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PMID:Principal drug-metabolizing enzyme systems in L1210 leukemia sensitive or resistant to BCNU in vivo. 796 9

Numerous studies performed in vitro have suggested a role for glutathione (GSH) in determining the sensitivity/resistance of tumour cells to various platinum-based drugs. Few studies have extended these findings into the in vivo setting. We have measured GSH levels in two murine (ADJ/PC6 plasmacytoma and L1210 leukaemia and their acquired platinum-drug-resistant sublines) and five human ovarian carcinoma (PXN/100, PXN/109T/C, SKOV3, HX/62 and OVCAR-3) tumour models of varying sensitivity to cisplatin. Results showed that relatively high GSH levels may be involved, at least partially, in determining platinum drug resistance in vivo in at least some of the tumour models studied (ADJ/PC6 carboplatin and tetraplatin resistant tumours; L1210 cisplatin and tetraplatin resistant tumours and the HX/62 and OVCAR-3 human ovarian carcinoma xenografts). However, in other tumours (e.g., the acquired cisplatin resistant ADJ/PC6 plasmacytoma) non-GSH mediated mechanisms of resistance (such as enhanced DNA repair) probably account for the resistance. Pretreatment of animals with oral buthionine sulfoximine (BSO), which resulted in approximately 70% depletion in tumour GSH levels, failed to potentiate the antitumour efficacy of either cisplatin (using the ADJ/PC6 and L1210 models) or the 1,2-diaminocyclohexane (DACH) platinum-drug, tetraplatin (using the ADJ/PC6 model). These BSO plus or minus cisplatin data suggest a limited role for such combinations in the clinic.
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PMID:The role of glutathione (GSH) in determining sensitivity to platinum drugs in vivo in platinum-sensitive and -resistant murine leukaemia and plasmacytoma and human ovarian carcinoma xenografts. 807 51

Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient rs = 0.38, p < 0.04), melphalan (rs = 0.39, p < 0.04) and prednisolone (rs = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thioguanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevation of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.
Leukemia 1994 Sep
PMID:Raised intracellular glutathione levels correlate with in vitro resistance to cytotoxic drugs in leukaemic cells from patients with acute lymphoblastic leukemia. 809 28

Overnight (10-16 h) incubation of retinoic acid (RA), a derivative of vitamin A, specifically induced LTC4 synthase activity (5 to 10-fold), but not LTA4 hydrolase activity in the lysate of rat basophilic leukemia-1 (RBL-1) cells. A time course study revealed that the increase of LTC4 synthase activity was time dependent and that the peak value was obtained after a 24-hour incubation with RA. The induction of enzyme activity was specifically localized to the microsomal fraction. Glutathione (GSH) S-transferase activity measured by using the same cell lysate as an enzyme source and 1-chloro-2,4-dinitrobenzene (DNCB) as a substrate was not influenced by RA treatment, indicating that the induction by RA is specific for membrane-bound LTC4 synthase. The induction of LTC4 synthase may be an important regulatory mechanism of peptide-LT synthesis in allergy and inflammatory diseases.
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PMID:Specific induction of LTC4 synthase by retinoic acid in rat basophilic leukemia-1 cells. 811 Dec 44


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