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)

L1210 leukemia is a murine leukemia which is associated with anemia and marked neutrophilia. In order to determine the significance of free radicals (FR) in this disorder, we determined the presence and localization of free radical scavengers (FRS) and scavenger-like systems in L1210 leukemia cells obtained in vivo and from in vitro cultures. FR are metabolized or detoxified by certain FRS such as glutathione (GSH and GSSG), superoxide dismutase (SOD) and enzymes such as epoxide hydrolase (EH). In all cases specific fractions of L1210 cells, bone marrow and liver were examined for FR/FRS levels. Reduced (GSH) and oxidized (GSSG) glutathione were measured fluorometerically using o-opthalaldehyde (OPT). SOD was determined colorimetrically utilizing pyrogallol by substrate autolysis inhibition, and EH was determined by utilizing [3H] styrene oxide as a substrate. Ratios of GSH/GSSG in fractions prepared from in vivo and in vitro L1210 cells showed a predominance of GSH-reductase with the highest activity in mitochondria (ratio = 15 vs. 10). Normal liver showed a similar pattern whereas, leukemic liver showed altered GSH/GSSG ratios in mitochrondria and microsomes. Leukemic bone marrow showed a predominance of GSH-reductase in all fractions. EH activity was highest in microsomal fractions obtained from L1210 cells grown in vitro and found to become increased in both the mitrochondrial (100%) and microsomal (200%) fractions when cells were exposed to retinoic acid (RA) in culture. SOD activity in the cytosolic (21.2 U SOD/mg) and mitochondrial (12 U SOD/mg) fractions whereas, leukemic liver showed a significant decrease in activity in all fractions compared to normals. SOD was determined in fractions taken from L1210 cells in vivo and in vitro. Results demonstrated detectable but reduced SOD activity in the L1210 cell fractions as contrasted with liver activity. Results from these studies indicate that certain FRS systems are functional in L1210 leukemic animals. Furthermore, variations in the ratios or levels may be of significance in the leukemic and hematological states.
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PMID:The significance of free radicals and free radical scavengers in L1210 leukemia. 322 4

The glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO) was tested for cytotoxicity and thiol depletion in murine and human tumor cells in vitro, and for its antitumor activity and toxicity in vivo. The cell lines used in these studies included murine L-1210 leukemia, human RPMI 8226 myeloma, MCF-7 breast cancer and WiDr colon carcinoma. Soft agar colony forming assays showed that BSO was most effective at reducing tumor colony formation when exposed continuously to cells in vitro. Drug concentrations which inhibited colony formation to 50% of control levels ranged from 2.0-6.2 mM (for 1 hour exposures), 2-100 mM for 24 hour exposures and 0.4-1.40 microM (for continuous BSO exposures). Human myeloma cells proved most sensitive to BSO. In vitro cytotoxicity correlated with depletion of intracellular nonprotein sulfhydryls to less than or equal to 10% of control values in both L-1210 and 8226 cells. This was routinely achieved with prolonged exposures to mM BSO concentrations for greater than 24 hours. Normal mice tolerated high BSO doses (up to 5.0 g/kg) without evidence of acute toxicity. BSO was not active against L-1210 leukemia-bearing DBA/2 mice. When tested in vivo against MOPC-315 plasmacytoma-bearing BALB/c mice, BSO was not active at doses up to 4.0 g/kg. In contrast, the bifunctional alkylating agent melphalan (L-PAM) was active against MOPC-315 and this activity was enhanced by a 24 hour pretreatment of mice with 50 mg/kg of L-BSO.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytotoxic effects of glutathione synthesis inhibition by L-buthionine-(SR)-sulfoximine on human and murine tumor cells. 358 42

Murine L1210 leukemia cells resistant to the antineoplastic agent L-phenylalanine mustard have a 1.5-2.0-fold elevation in their cellular GSH and GSSG content as compared to drug-sensitive cells. Cellular uptake of L-[U-14C]cystine and its incorporation into GSH of the resistant tumor are correspondingly elevated. Synthesis of gamma-glutamylcysteine, GSH, and GSSG is elevated 1.5-2.0-fold in cell-free preparations of the resistant tumor. This increased synthesis of GSH is attributed to increased cellular content (1.6-fold) of gamma-glutamylcysteine synthetase. GSH synthetase activity is equivalent in both drug-sensitive and -resistant cells. Investigation into the hydrolysis of selected peptides by cell-free preparations of both sensitive and resistant tumors suggest that aminopeptidase M participates in the formation of L-cysteine from L-Cys-Gly. This is supported by the observation that these preparations readily degrade L-Leu-p-nitroanilide and L-Ala-L-Ala-L-Ala, known substrates for aminopeptidase M, but not dipeptidase. The failure of the tumors to degrade Gly-D-Ala, a dipeptidase substrate, and the marked inhibition of L-Ala-Gly, L-Cys-Gly, and L-Ala-L-Ala-L-Ala hydrolysis by Bestatin further support a role for aminopeptidase M in the generation of L-cysteine from L-Cys-Gly. These results suggest that the drug-resistant tumor cell has developed an efficient mechanism for maintenance of elevated GSH which involves both gamma-glutamyl transpeptidase-initiated catabolism of GSH to cysteine and its reutilization by gamma-glutamylcysteine synthetase.
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PMID:Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells. 366 23

Metastatic migration of murine L1210 leukemia cells, sensitive and resistant to the antitumor agent L-phenylalanine mustard, from the peritoneal cavity of mice to the liver resulted in a 2-fold elevation in their GSH content. This increase in GSH was accompanied by a corresponding increase in their resistance to the drug. Cell surface binding studies with the non-penetrating disulfide, 6,6'-dithiodinicotinic acid, indicated that both tumors isolated from the liver had a greater than 5-fold elevation in surface sulfhydryls when compared to their ascitic counterparts. These results indicate a role for the hepatic microenvironment in the maintenance of tumor cell GSH, drug responsiveness, and surface sulfhydryls.
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PMID:Hepatic-mediated elevation and maintenance of metastatic tumor cell glutathione. 370

Glutathione (GSH) plays a crucial role in the protection of normal and tumor tissue against the toxic effects of numerous chemotherapeutic drugs. Therefore, the possible therapeutic benefit of thiol depletion in cancer treatment is dependent upon the relative degree to which tumor or normal tissue is sensitized to the toxic effects of subsequent chemotherapy. To address this issue, the following studies on the chemosensitization of melphalan (L-PAM) by the thiol-depleting agent buthionine sulfoximine (BSO) were conducted in vivo in BDF mice inoculated with L-PAM-resistant murine L1210 leukemia. Different dosing regimens of BSO were found to potentiate L-PAM toxicity in a manner that depended upon the degree of GSH depletion. Multiple i.p. injections of BSO (450 mg/kg every 6 h X 5) were found to reduce GSH concentrations in most tissues by 70-80%, and to decrease the LD50 for L-PAM from 22 to 14 mg/kg. No two organs were found to behave entirely the same with respect to the rate of depletion or recovery of GSH, or to the maximum depletion that could be obtained by BSO. In this regard, the bone marrow was found to be the most resistant tissue to thiol depletion by BSO and was found to tolerate the combination of BSO and therapeutic doses of L-PAM. However, BSO pretreatment markedly inhibited the recovery of the peripheral WBC population at the LD10 dose of L-PAM. Differences also were found in the in vivo metabolism of GSH by L-PAM-sensitive and -resistant murine L1210 leukemia cells. The intracellular concentration of GSH in the resistant cell line was 1.6-fold higher than in the sensitive tumor. Moreover, GSH levels were depleted more rapidly in the resistant tumor relative to the sensitive cell line. A single injection of BSO decreased GSH concentrations in both tumors to equivalent levels (20 nmol/10(7) cells) within 24 h. However, multiple i.p. injections of BSO failed to produce a significant increase in the life-span of L-PAM-treated animals despite a 90% reduction in tumor GSH concentrations (5.5 nmol/10(7) cells). In contrast to the median day survival data, BSO was found to enhance the antitumor activity of L-PAM as determined by an in vivo/in vitro clonogenic assay or by in vivo thymidine incorporation. Using decreased thymidine incorporation as an index of antitumor activity, BSO was found to increase the therapeutic index (LD10/ED50) of L-PAM from 3.6 to 6.5.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemosensitization of L-phenylalanine mustard by the thiol-modulating agent buthionine sulfoximine. 381 59

Since endogenous glutathione (GSH), the main non-protein intracellular thiol compound, is known to provide protection against reactive radical species, its depletion by diethylmaleate (DEM) was used to assess the role of free radical formation mediated by doxorubicin in DNA damage, cytotoxicity and mutagenicity of the anthracycline. Subtoxic concentrations of DEM that produced up to 75% depletion of GSH did not increase doxorubicin cytotoxicity in a variety of cell lines, including Chinese hamster ovary (CHO) and lung (V-79) cells, LoVo human carcinoma cells and P388 murine leukemia cells. Similarly, the number of doxorubicin-induced DNA single strand breaks in CHO cells and the mutation frequency in V-79 cells were not affected by GSH depletion. The results obtained suggest that mechanisms other than free radical formation are responsible for DNA damage, cytotoxicity and mutagenicity of anthracyclines.
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PMID:Lack of effect of glutathione depletion on cytotoxicity, mutagenicity and DNA damage produced by doxorubicin in cultured cells. 395 90

When basophils or mast cells are stimulated by a specific antigen they release chemical mediators, including a potent bronchoconstrictor, slow reacting substance of anaphylaxis (SRS-A). The structure of SRS from a mouse mastocytoma and rat basophilic leukaemia (RBL-1) cells has been identified as a thioether or arachidonic acid and glutathione [not a thioether of cystene as was originally thought]. SRS has been named leukotriene (LT) C and may be formed by a novel lipoxygenase pathway which also synthesizes 5,6-oxido-7,9,11,14-icosatetraenoic acid (LTA) and 5,12-dihydroxy-6,8,10,14-icosatetraenoic acid (LTB). Homogenates of RBL-1 cells, when incubated with C-arachidonic acid, form 5-hydroxy-icosatetraenoic acid (5-HETE) and 5,12-dihydroxy- and 5,6-dihydroxy-icosatetraenoic acid. The latter is the spontaneous breakdown product of the labile intermediate LTA. Formation of both compounds is stimulated by calcium. We have now produced biologically active SRS in a cell-free system generated from RBL-1 cells. Glutathione was essential for SRS synthesis and calcium stimulated its formation.
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PMID:Enzymatic assembly of slow reacting substance. 610 62

To further elucidate the role of glutathione (GSH) in the biosynthesis of slow reacting substance (SRS), SRS generation was studied in rat basophilic leukemia cells that had been preincubated with 2-cyclohexen-1-one or diethyl maleate to decrease their intracellular GSH concentrations. At low GSH levels SRS formation was markedly inhibited. The formation of other lipoxygenase products was much less affected, although some decrease in 5-hydroxyicosatetraenoic acid formation also occurred, apparently due in part to less rapid reduction of the 5-hydroperoxide.
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PMID:Relationship of biosynthesis of slow reacting substance to intracellular glutathione concentrations. 610 85

Under strongly basic conditions [excess LiOH, dimethoxyethane/water (4:1, vol/vol)], purified slow reacting substances (SRSs) SRS-GSH and SRS-Cys were not isomerized to their corresponding 11-trans isomers. However, addition of thiols such as glutathione (GSH) or L-cysteine to this basic medium produced various amounts of 11-trans-SRS, depending on the thiol concentration. This chemical isomerization was inhibited by the radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidinooxy free radical (HTMP); the inhibition suggests that the thiyl radical (RS) is added reversibly to the triene system at C-12, resulting in the overall cis leads to trans isomerization of the 11,12 double bond. Because the amount of 11-trans-SRS-Cys produced by intact rat basophilic leukemia (RBL-1) cells was consistently higher than the amount produced in boiled cells, we believe that intact RBL-1 cells contain enzyme systems that form peroxides, which are known to enhance the formation of thiyl radicals, required for cis leads to trans isomerization. Likewise, HTMP inhibited the formation of 11-trans-SRS-Cys in this cell system.
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PMID:Formation of 11-trans slow reacting substances. 611 46

Elevated levels of polyamines and gamma-Glutamyl Transpeptidase were seen in the liver of P388 leukemia bearing mice. There was also increase in specific activity of beta-Hexosaminidase and the B/A isoenzyme ratio. Administration of a 2% solution of alpha-Difluoromethylornithine (DFMO) immediately after inoculation of tumor cells prevented increases in polyamines in liver, but did not have any effect on gamma-Glutamyl Transpeptidase. Almost normal ratio of beta-Hexosaminidase B to A was maintained during treatment. Endogenous ornithine level was not altered both in treated and untreated mice. However, proline level was elevated in liver of untreated mice and DFMO prevented this increase. Glutathione levels were altered both by leukemia and DFMO in the host liver. The effect of drug was more prominent in the early stages rather than during terminal stages of leukemic growth.
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PMID:Host liver changes in leukemic mice: effect of alpha-difluoromethyl ornithine, an inhibitor of polyamine synthesis. 615 40


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