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)

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

Tetraplatin (Ormaplatin) has good antitumor activity against some cisplatin-resistant cells and is currently being studied in clinical trials. We have studied the effect of extracellular reduced glutathione (GSH) on the cytotoxicity and biochemical pharmacology of tetraplatin in L1210 leukemia cells. Parent L1210/0 cells were exposed to tetraplatin for 2 hr with or without GSH in Hanks' balanced salt solution (HBSS), and cytotoxicity was assessed by a soft agar clonogenic assay. GSH (10 or 100 microM) increased tetraplatin (10 microM)-induced cell kill by about 2 logs; concentrations of the thiol 10-fold below or above these levels increased cell kill to a lesser degree. GSH-mediated increases in the cytotoxicity of tetraplatin were also observed against cisplatin-resistant L1210/DDP and tetraplatin-resistant L1210/DACH cells. An equimolar concentration of 1,2-diaminocyclohexane-platinum(II) dichloride [DACH-Pt(II)Cl2] alone was as cytotoxic as the combination of tetraplatin and GSH. Intracellular accumulations of tetraplatin in both L1210/0 and L1210/DDP cells were increased by GSH, whereas in L1210/DACH cells platinum uptake decreased in the presence of the thiol. Reactions between tetraplatin and salmon sperm DNA in the presence or absence of GSH (1 or 100 microM), performed at 37 degrees in HBSS, revealed that levels of total and interstrand DNA-platinum adducts were minimal in the absence of GSH, whereas in the presence of GSH DNA adducts of tetraplatin were substantial and similar to those seen with DACH-Pt(II)Cl2. Tetraplatin (10 microM) incubated at 37 degrees in HBSS with GSH (10 microM-1 mM) was reduced chemically to the DACH-Pt(II) species within 5 min; a 200-microM tetraplatin solution required a GSH concentration of at least 100 microM for substantial reduction to occur. This chemical reduction of tetraplatin appears to be a prerequisite for its biological activity. Thus, extracellular GSH can modulate the biological activity of tetraplatin, and the combination may prove useful in specific clinical applications, such as intracavitary platinum therapy.
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PMID:Glutathione-mediated modulation of tetraplatin activity against sensitive and resistant tumor cells. 818 78

Accumulating evidence suggests a critical role of intracellular glutathione in tumor cell resistance to alkylating agents. The present study provides evidence for the direct interaction between cis-diamminedichloroplatinum(II) (cisplatin) and glutathione (GSH) both in a cell-free system, as well as in L1210 murine leukemia cells. We have isolated the reaction product and identified it by a combination of high performance liquid chromatography and atomic absorption spectroscopy. Stoichiometric analysis showed a 2:1 molar ratio of GSH/cisplatin for the reaction. The molecular mass assessed by mass spectroscopy was 809 Da, corresponding to a GS-platinum chelate complex, bis-(glutathionato)-platinum. The GS-platinum complex was detected in L1210 leukemia cells incubated with 20 microM cisplatin. The intracellular content of the GS-platinum complex reached a maximal level after 12 h, corresponding to about 60% of the intracellular platinum content. Thus, formation of the GS-platinum complex is considered a significant part of the cellular metabolism of cisplatin. The GS-platinum was found to inhibit cell-free protein synthesis in a rabbit reticulocyte lysate system using both chloramphenicol acetyltransferase mRNA and poly(A) mRNA from HL-60 human promyelocytic leukemia cells (IC50 = 190 microM the GS-platinum complex). Elimination of the GS-platinum complex from tumor cells may represent an important mechanism which reduces the intracellular accumulation of the platinum complex. Using plasma membrane vesicles prepared from L1210 cells, the transport of the GS-platinum complex across the plasma membrane was found to be an ATP-dependent process (apparent Km values: 49 microM, ATP; 110 microM, GS-platinum complex). The ATP-dependent transport of the GS-platinum complex was inhibited by vanadate (IC50 = 35 microM) as well as by S-(2,4-dinitrophenyl)-glutathione, leukotriene C4, and GSSG, but not by doxorubicin, daunorubicin, or verapamil. The ATP-dependent glutathione S-conjugate export pump, "GS-X pump" (Ishikawa, T. (1992) Trends Biochem. Sci. 17, 463-468), is suggested to play a role in the elimination of the GS-platinum complex from tumor cells.
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PMID:Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. 837 70

Exposure of humans and experimental animals to benzene has been shown to result in hematotoxicity such as pancytopenia, aplastic anemia, and leukemia. The oxidative activation of the benzene metabolite, hydroquinone (HQ), in the bone marrow to the electrophilic benzoquinone (BQ) has been suggested to play an important role in benzene-induced hematotoxicity. Since the interaction of several xenobiotics with copper has been shown to result in their metabolism, in this study we have investigated the role of copper in the oxidation of HQ and HQ-induced toxicity to mice bone marrow stromal cells, target cells of HQ in the bone marrow. In phosphate-buffered saline, HQ underwent autoxidation slowly to BQ, while the presence of Cu(II) ions (1, 2.5, 5, 10, 50 microM) strongly accelerated the oxidation of HQ to BQ in a concentration-dependent manner. Reaction of HQ with Cu(II) was also accompanied by the reduction of Cu(II) to Cu(I), the utilization of O2, and the concomitant generation of H2O2. The oxidation of HQ by Cu(II) could be blocked by the Cu(I)-specific chelator bathocuproinedisulfonic acid (BCS), particularly when the ratio of BCS to Cu(II) was 4:1. By observing the kinetics of the reactions derived from mixing 100 microM HQ and 100 microM Cu(II), it was found that all of the Cu(II) was reduced to Cu(I) within 5 s, followed by consumption of O2 and the generation of BQ, which reached maximum levels at 4 min after mixing HQ and Cu(II). In addition, oxidation of HQ by Cu(II) also generated chemiluminescence. In the presence of myeloperoxidase, Cu(II)-mediated oxidation of HQ was increased. Addition of Cu(II) to primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity. The enhanced cytotoxicity of HQ by Cu(II) could be completely prevented by adding BCS, glutathione (GSH), or dithiothreitol but not by catalase. Supplementation of stromal cells with 20 microM BCS in the absence of exogenously added Cu(II) significantly abated HQ-induced cellular GSH depletion and cytotoxicity, suggesting a possible involvement of endogenous copper in the activation of HQ. The above results indicate that Cu(II) strongly induces the oxidation of HQ and as such may be a factor involved in the oxidative activation and toxicity of HQ in target cells.
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PMID:Oxidation of hydroquinone by copper: chemical mechanism and biological effects. 842 68

N-deformyl-N-[4-N,N-bis(2-chloroethylamino)benzoyl] distamycin-A (FCE 24517) is a new cytotoxic anti-tumor agent in phase-1 clinical trials. We have isolated stable FCE-24517-resistant cell sublines from murine leukemia L1210 cells by in vitro exposure to the drug. FCE 24517 selects a mixed population of resistant cells: the L1210/24517(1) cell line in vitro was in fact resistant to the selecting agent (RI 48.3), as well as to L-PAM (RI 5.4) and DX (RI 8.6) and over-expressed the mdr-I gene. When L1210/24517(1) cells were implanted in vivo and evaluated for sensitivity to the same agents, resistance was observed only to FCE 24517 and partially to L-PAM, whereas DX had the same anti-tumor efficacy as on the sensitive line. The clone derived from the above subline (L1210/24517(2)) was resistant to FCE 24517, distamycin-A and other cytotoxic compounds bearing the distamycin-A skeleton, and fully sensitive to DX and other anti-tumor compounds involved in the multi-drug resistance mechanisms, with a complete disappearance of the mdr phenotype. L1210/24517(2) cell line is partially cross-resistant to L-PAM, this resistance being accounted for by higher GSH intracellular levels, which however do not influence the resistance to FCE 24517. In fact, BSO treatment was capable of significantly modifying only the cytotoxicity of L-PAM. Our data suggest that L1210/24517(2) cells present a mechanism of resistance specific for FCE 24517 and related molecules.
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PMID:Establishment of L1210 leukemia cells resistant to the distamycin-A derivative (FCE 24517): characterization and cross-resistance studies. 842 70

Merocyanine 540 (MC540) is a lipophilic photosensitizing dye of biomedical interest in connection with its ability to preferentially inactivate leukemia cells in bone marrow grafts and enveloped viruses in blood products. Evidence that iron plays a role in dye-mediated photokilling is presented in this report. When sensitized with MC540 and irradiated with visible light, cultured murine leukemia L1210 cells underwent lipid peroxidation (accumulation of iodometrically detectable lipid hydroperoxides) and photokilling (loss of clonogenic capacity). Selenium-deficient [Se(-)] cells, which expressed minimal selenoperoxidase activity, were found to be more sensitive to photoperoxidation and photokilling than selenium-replete [Se(+)] controls. Since redox active iron in the presence of electron donors has been shown to exacerbate photoperoxidative damage in isolated membrane systems, it was of interest to examine the possible role of iron in MC540/light-induced cytotoxicity. Involvement of iron was established by showing (i) that desferrioxamine (a high-affinity chelator and redox inhibitor of Fe3+) acted protectively on Se(-) and Se(+) cells and (ii) that treating these cells with sublethal concentrations of the lipophilic chelate ferric 8-hydroxyquinoline [Fe(HQ)2] made them much more sensitive to photokiling and thiobarbituric acid-detectable lipid peroxidation. Lehal damage induced by t-butyl hydroperoxide was also amplified by Fe(HQ)2. Fe(HQ)2-enhanced photoperoxidation and photokilling were suppressed by alpha-tocopherol, suggesting that iron-catalyzed free radical reactions were involved. A mechanism based on iron-mediated one-electron reduction of nascent photoperoxides is proposed. We believe that under the conditions used, toxic one-electron chemistry overwhelms two-electron detoxification catalyzed by GSH-dependent selenoperoxidase(s).
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PMID:Photodynamic action of merocyanine 540 on leukemia cells: iron-stimulated lipid peroxidation and cell killing. 843 51


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