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 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

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

Red cell reduced glutatione (GSH) and pyrimidine 5'-nucleotidase (Pry 5'-NT) were measured in a variety of myeloproliferative and lymphoproliferative disorders. Raised levels of GSH were found in chronic lymphocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinaemia and myeloma. Decreased activity of Pyr 5'-NT was found in acute myeloblastic leukaemia, acute lymphoblastic leukaemia, chronic granulocytic leukaemia, chronic lymphocytic leukaemia, Hodgkin's disease and non-Hodgkin's lymphoma. There was no correlation between the raised GSH levels and decrease Pry 5'-NT levels.
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PMID:Red cell pyrimidine 5'-nucleotidase and glutathione in myeloproliferative and lymphoproliferative disorders. 624 15

Rat basophilic leukemia cells have frequently been employed for investigating the pathways of leukotriene biosynthesis, a class of biologically active arachidonic acid metabolites. However, information is lacking on the levels of selenium-dependent glutathione peroxidase (Se-GSH-Px), non-Se-GSH-Px and glutathione S-transferases (GSH-S-Trs), key enzymes involved in fatty acid hydroperoxide metabolism and leukotriene biosynthesis in these cells. Both GSH-S-Trs and non-Se-GSH-Px reactions are catalyzed by the same enzyme. In the present studies, we have measured the enzyme activities of GSH-Px(s) and GSH-S-Trs in the 105,000 X g supernatant fraction of sonified RBL-1 cells. The specific activities for GSH-Px(s) toward H2O2, cumene hydroperoxide, and 15S-hydroperoxy-eicosatetraenoic acid (15S-HPETE) are 12.6, 17.9 and 26.9 nmoles X min-1 X mg-1 protein, respectively. A specific activity of 18.9 nmoles X min-1 X mg-1 protein with 1-chloro-2,4-dinitrobenzene was estimated for the GSH-S-Trs. Therefore, the cell fraction that exhibits 5-lipoxygenase activity also contains selenium and non-selenium glutathione peroxidases.
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PMID:Measurement of glutathione requiring enzymes involved in arachidonic acid cascade of rat basophilic leukemia cells. 644 77

The cytostatic unsaturated ketonucleosides, 1, 2, 3 and 4 are highly reactive sulfhydryl blocking agents. Kinetics of their reactions with reduced glutathione (GSH) were measured and their reactivity was compared to that of N-ethylmaleimide (NEM), acrylonitrile and chloroacetamide. Their reaction products with N-acetyl-L-cysteine (AcCys) were prepared and characterized by chemical analysis and nuclear magnetic resonance (NMR) spectroscopy. Compounds 1, 2 and 3 gave Michael type 1:1 addition products. Compound 4 reacted with AcCys by a three step mechanism; the primary addition product 8 underwent an unusual elimination reaction giving the unsaturated compound 9, which yielded the addition product 10 with AcCys. In the reaction with GSH, compound 4 behaved like a bifunctional SH alkylating agent. Compounds 1, 2, 3 and 4 also reacted with protein thiols as shown by their ability to inhibit lactate dehydrogenase (LDH). Unsaturated ketonucleosides had diversified effect on L1210 leukemia cells. While the most potent cytostatics, compounds 1 and 3, reduced considerably the membrane surface SH level, they were without effect on soluble intracellular protein thiols. In contrast, nucleosides 2 and 4, less active than the former, only slightly affected the membrane surface sulfhydryls and considerably depleted the intracellular soluble protein thiols. Only slight differences were found between the reactions of the four nucleosides with non-protein SH (NPSH). The correlation found between in vivo biological activity and cell membrane impairment suggests that selective alkylation of certain key membrane thiols by unsaturated ketonucleosides might be an important event in their biological effect.
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PMID:Interactions of cytostatic unsaturated ketonucleosides with sulfhydryl containing cell constituents. 661 5

Pretreatment of Swiss mice and Sprague-Dawley rats with glutathione (GSH) reduced the acute lethal toxicity of cis-dichlorodiammine platinum (II) (cis-DDP) in a dose-dependent manner. The protection was accompanied by reduction of both body weight loss and by reduction of nephrotoxicity, as measured by a rise in serum blood urea nitrogen (BUN), creatinine levels and by histopathologic changes, which occurred 4 days following cis-DDP treatment. The antitumor effects of cis-DDP on experimental tumor models (P388 and Gross leukemia) were not significantly altered by GSH treatment. It is suggested that the partial protection by GSH from acute toxicity of the antitumor drug is directly related to protection of renal function.
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PMID:Protective effect of reduced glutathione against cis-dichlorodiammine platinum (II)-induced nephrotoxicity and lethal toxicity. 668 12


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