Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Hydroperoxycyclophosphamide (4-HC) is widely used as an ex vivo bone marrow purging agent for acute myeloid leukemia (AML) blasts. We have determined the effect of a combined treatment with interleukin 3 (IL-3) plus IL-6 on 4-HC cytotoxicity against normal (CFU-GEMM) versus AML (L-CFU) bone marrow progenitor cells. Following an 18 h exposure to IL-3 plus IL-6, treatment with 4-HC in conjunction with IL-3 and IL-6 for one hour resulted in a significantly greater inhibition of L-CFU versus CFU-GEMM colony growth. In addition, treatment with IL-3 plus IL-6 reduced the inhibitory effects of higher concentrations of 4-HC on CFU-GEMM but not L-CFU growth. IL-3 and IL-6 did not protect the self-renewing, clonogenic, AML blast progenitor cells from the cytotoxic effects of 4-HC. While the total intracellular glutathione (GSH) levels were not significantly different between untreated normal bone marrow mononuclear cells (NBMMC) and AML blasts, greater intracellular GSH-S transferase activity was observed in the NBMMC. 4-HC produced a marked reduction in GSH levels in NBMMC as well as AML blasts. But treatment with IL-3 plus IL-6 in conjunction with 4-HC resulted in significantly higher GSH levels in NBMMC. These differences in intracellular GSH levels and GST activity may offer an explanation for the differential protective effects of IL-3 plus IL-6 treatment against the cytotoxic effects of 4-HC on CFU-GEMM colony growth.
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PMID:Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclophosphamide-mediated reduction of glutathione levels and cytotoxicity in normal and leukemic bone marrow progenitor cells. 164 Jul 34

The suppressive effect of L-ascorbic acid on the growth of bone marrow cells from patients with acute nonlymphocytic leukemia was studied using a modified agar culture method featuring daily feeding to allow the growth of leukemic cell colonies. In seven of 28 patients (25%), the numbers of leukemic cell colonies grown in culture were reduced to 21% of control by the addition of L-ascorbic acid (0.3 mM) to the culture medium. Glutathione did not suppress leukemic cell colonies although it has a similar oxidation-reduction potential to that of L-ascorbic acid. The addition of L-ascorbic acid reduced the pH of the medium. However, a comparable reduction of pH by the addition of HCl did not suppress leukemic cell colonies. In simultaneous cultures for leukemic and normal marrow cells, the suppression of leukemic cell colony was noted with a concentration of L-ascorbic acid as low as 0.1 mM (a concentration achievable in vivo), but normal myeloid colonies were not suppressed until the concentration of L-ascorbic acid reached an extremely high level (1 mM). In conclusion, growth of leukemic cells in culture was suppressed by L-ascorbic acid in a substantial proportion of patients with acute nonlymphocytic leukemia. This suppression was a specific effect of L-ascorbic acid and was not due to its oxidation-reduction potential or pH change. Leukemic cells were selectively affected at an L-ascorbic acid concentration attainable in vivo while normal hemopoietic cells were not suppressed.
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PMID:Growth suppression of human leukemic cells in vitro by L-ascorbic acid. 692 98

The ectoenzyme gamma glutamyltransferase (GGT) a second messenger generating enzyme activity on the cytoplasmic membrane was biochemically analyzed in leukemic cells from patients with acute lymphoblastic and myeloid leukemias. The lower mean activity--0.594 IU/mg protein was noticed in patients with acute lymphoblastic leukemias (ALL), while the higher--0.956 IU/mg protein was found in acute myeloid leukemia patients (AML) in serum and 0.151 IU/mg protein in polymorphonuclear cells. The levels of the activity of glutathione reductase (GR) were increased but the activities of glutathione peroxidase (GSH Px) were significantly decreased in serum of leukemia patients.
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PMID:Activities of enzyme transducing extracellular signals--gamma glutamyltransferase and enzymes metabolizing glutathione in acute lymphoblastic and myeloid human leukemias. 761 77

Cytosine arabinoside is usually considered to be lethal by incorporation into DNA followed by chain termination. Recently, we have reported that the radical scavenger N-acetyl-cysteine (NAC) protects cultured clonogenic AML blast cells from the lethal affects of Ara-C if given before the drug. This observation provides indirect evidence that toxic reactive oxygen intermediates (ROI) are generated in AML blast cells following Ara-C-induced damage to DNA. In the present paper we present evidence in support of this hypothesis. Using flow cytometry and multiple fluorescent probes for live cell function, we have mapped a sequence of discrete stages that occur during Ara-C cytotoxicity. An early event was the increased generation of ROI. Initially this oxidative stress was countered by an increase in the cellular content of reduced glutathione (GSH), but cells then underwent an abrupt transition to a state characterized by low GSH and very high ROI generation indicative of collapse of cellular redox balance. Next, the capacity to maintain low intracellular ionized calcium was lost, probably due to lipid peroxidation at membrane sites of calcium regulation. Finally, surface membrane integrity was lost. Concurrent measurements of clonogenic cell survival insured the relevance of these flow cytometry measurements to the stem cell population. We used OCI/AML-2 cells transfected with bcl-2 to look for the place in this sequence where bcl-2 protein protects cells against apoptosis; bcl-2 transfectants showed an increase in ROI generation similar to controls, but were able to maintain GSH levels in the face of this oxidative stress. We conclude that oxidative stress plays a major role in Ara-C toxicity, and that bcl-2 protein protects cells by maintaining cellular redox balance in a reducing state. These studies complement previous work showing how regulators of AML growth affect the sensitivity of blast cells to Ara-C by changing the concentration or stability of bcl-2 protein.
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PMID:Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. 868 94

Drug resistance often results in failure of anticancer chemotherapy in leukemias. Several mechanisms of drug resistance are known with multidrug resistance (MDR) being the best characterized one. MDR can be due to enhanced expression of certain genes (MDR1, MRP or LRP), alterations in glutathione-S-transferase activity or GSH levels and to reduction of the amount or the activity of topoisomerase II. Here we review the current status of the clinical significance of the various mechanisms of MDR in leukemias and also discuss possibilities for the reversal of MDR. MDR1 gene expression has been seen in many leukemias, notably in acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia. Both MDR1 RNA and P-glycoprotein expression of the leukemic cells have been shown to correlate with poor clinical outcome in AML. However, preliminary results indicate that the MRP gene as well as the LRP gene can be expressed in AML. Thus, drug resistance in leukemias appears to be multifactorial. P-glycoprotein-mediated MDR can be reversed by several drugs. These resistance modifiers are currently evaluated with regard to their clinical efficacy. Despite some encouraging results, reversal of drug resistance and subsequent improvement in clinical outcome remains to be shown.
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PMID:Multidrug resistance in leukemias and its reversal. 903 Oct 75

The mitochondrial permeability transition and oxidative stress seem to be critical alterations in cellular physiology that take place during programmed cell death. Failure to undergo apoptosis is associated with drug resistance in acute myeloid leukemia and other cancers. Therefore, it is important to establish causal relationships between the physiological changes that take place in apoptosis, because these are potential targets for novel treatment strategies to overcome this form of drug resistance. We describe the use of multilaser flow cytometry methods to make correlated measurements of mitochondrial membrane potential (MMP), the generation of reactive oxygen intermediates, the cellular content of reduced glutathione (GSH), intracellular calcium, and exposure of phosphatidylserine on the cell surface. Using these combined methods, we have mapped a "death sequence" that occurs after treatment of leukemic blasts with clinically relevant concentrations of 1-beta-D-arabinofuranosylcytosine (ara-C). Dual labeling of MMP and cellular glutathione content showed that loss of MMP, indicative of the permeability transition, took place in cells that were depleted of glutathione. The loss of MMP coincided with phosphatidylserine exposure and preceded a state of high reactive oxygen generation. Finally, there was an increase in intracellular calcium. These results demonstrate that the mitochondrial permeability transition takes place during ara-C toxicity but suggest that this occurs downstream of the loss of GSH. Thus, oxidative stress after ara-C-induced toxicity seems to be a biphasic phenomenon, with the permeability transition occurring after a depletion of GSH and preceding a state of high reactive oxygen generation.
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PMID:Relationships between the mitochondrial permeability transition and oxidative stress during ara-C toxicity. 919 24

In order to better understand acquired resistance to antitumor agents in acute myelogenous leukemia (AML), we investigated various drug resistance mechanisms; namely, topoisomerase II (topo II), glutathione system and P-glycoprotein (P-gp). Blast cells of 31 patients with AML, 21 before treatment (BT) and 10 at relapse (AR) were studied. Topo II was evaluated by Western blot analysis. Glutathione-S-transferase activity (GST) and glutathione content (GSH) were investigated by spectrophotometric assays. GST isoenzymes (-alpha, -mu and -pi) were tested by Western blot and by immunocytochemical staining. P-gp was evaluated by an immunocytochemical method using MRK 16 antibody. Our results showed that GST, GSH and GST-pi were similar in patients BT and AR GST-mu was detected in 13/21 AML BT and in 5/10 AML AR. GST-alpha expression was higher (p < 0.05) in AML AR (60 +/- 105 AU/mg) compared to AML BT (10 +/- 10 AU/mg). A relationship was found between GST-pi quantitation evaluated by Western blot and immunocytochemical staining, whereas no correlation was observed for the other isoenzymes. Topo II was detected in only 4 AML BT and 3 AML AR. Eleven out of 21 AML BT and 3/10 AML AR expressed P-gp with immunohistochemical study. These results indicate that only the "glutathione system", especially the GST-alpha could be involved in drug resistance in AML.
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PMID:Glutathione system, topoisomerase II level and multidrug resistance phenotype in acute myelogenous leukemia before treatment and at relapse. 949 83

The glutathione-depleting agent buthionine sulfoximine (BSO) was found to be toxic to some AML blast populations. This toxicity was manifested as the appearance of high levels of reactive oxygen generation in GSH-depleted cells, and later by the loss of mitochondrial membrane potential and an increase in intracellular calcium. Striking heterogeneity in BSO sensitivity was observed in a series of four human AML cell lines, and in fresh leukemic blasts obtained from eight AML patients. In some cases, toxicity was seen at BSO concentrations as low as 1 microM; approximately 100-fold less than the plasma levels achieved in patients treated with BSO as a drug resistance reversing agent. Based on these results we propose that some AML blast populations are unusually dependent on GSH-based antioxidant mechanisms, due to high intrinsic rates of reactive oxygen generation. The mitochondrial respiratory chain is the most likely source of this reactive oxygen. Because toxicity is seen at clinically achievable concentrations of BSO, this agent might have antileukemic activity in patients.
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PMID:Antileukemic action of buthionine sulfoximine: evidence for an intrinsic death mechanism based on oxidative stress. 976 98

OCI/AML-2 acute myeloid leukemia cells were found to undergo apoptosis after treatment with y rays from a 137Cs source. Multilaser flow cytometry techniques using probes for live cell function were used to monitor the biochemical changes that occurred prior to the loss of surface membrane integrity. These showed increases in the generation of reactive oxygen species (ROS) and in the glutathione (GSH) content of irradiated cells. An additional population of cells that showed a further increase in ROS and depletion of GSH was seen in irradiated cells but not in controls. This population showed loss of mitochondrial membrane potential (deltapsim), indicative of the mitochondrial permeability transition, and exposure of phosphatidylserine on the cell surface. Increases in intracellular calcium were observed in a proportion of these low-deltapsi(m)/high-ROS cells. Similar findings were seen using the antileukemia drug cytosine arabinoside (ara-C), although cell cycle analysis showed that the loss of deltapsi(m) occurred mainly in G1 phase with ara-C treatment, and mainly in G2 phase with irradiation. Furthermore, the protective effect of overexpression of BCL2 was more pronounced after ara-C treatment than with radiation. Cells of the TP53 (formerly known as p53)-null human AML line OCI M2 showed growth arrest in G2 phase after radiation treatment, with no loss of deltapsi(m) or morphological changes indicative of apoptosis. The flavine-dependent oxidoreductase inhibitor diphenylene iodonium failed to inhibit generation of ROS in irradiated OCI/AML-2 cells, indicating that the mechanism is unlikely to involve the TP53-induced gene PIG3. These results show that oxidative stress can occur in irradiated human leukemia "blasts", and may play a direct role in radiation-induced apoptosis.
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PMID:An oxidative stress-mediated death pathway in irradiated human leukemia cells mapped using multilaser flow cytometry. 984 Jan 83

Etoposide (VP-16) is extensively used to treat cancer, yet its efficacy is calamitously associated with an increased risk of secondary acute myelogenous leukemia. The mechanisms for the extremely high susceptibility of myeloid stem cells to the leukemogenic effects of etoposide have not been elucidated. We propose a mechanism to account for the etoposide-induced secondary acute myelogenous leukemia and nutritional strategies to prevent this complication of etoposide therapy. We hypothesize that etoposide phenoxyl radicals (etoposide-O(.)) formed from etoposide by myeloperoxidase are responsible for its genotoxic effects in bone marrow progenitor cells, which contain constitutively high myeloperoxidase activity. Here, we used purified human myeloperoxidase, as well as human leukemia HL60 cells with high myeloperoxidase activity and provide evidence of the following. 1) Etoposide undergoes one-electron oxidation to etoposide-O(.) catalyzed by both purified myeloperoxidase and myeloperoxidase activity in HL60 cells; formation of etoposide-O(.)radicals is completely blocked by myeloperoxidase inhibitors, cyanide and azide. 2) Intracellular reductants, GSH and protein sulfhydryls (but not phospholipids), are involved in myeloperoxidase-catalyzed etoposide redox-cycling that oxidizes endogenous thiols; pretreatment of HL60 cells with a maleimide thiol reagent, ThioGlo1, prevents redox-cycling of etoposide-O(.) radicals and permits their direct electron paramagnetic resonance detection in cell homogenates. VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts. 3) Ascorbate directly reduces etoposide-O(.), thus competitively inhibiting etoposide-O(.)-induced thiol oxidation. Ascorbate also diminishes etoposide-induced topo II-DNA complex formation in myeloperoxidase-rich HL60 cells (but not in HL60 cells with myeloperoxidase activity depleted by pretreatment with succinyl acetone). 4) A vitamin E homolog, 2,2,5,7, 8-pentamethyl-6-hydroxychromane, a hindered phenolic compound whose phenoxyl radicals do not oxidize endogenous thiols, effectively competes with etoposide as a substrate for myeloperoxidase, thus preventing etoposide-O(.)-induced redox-cycling. We conclude that nutritional antioxidant strategies can be targeted at minimizing etoposide conversion to etoposide-O(.), thus minimizing the genotoxic effects of the radicals in bone marrow myelogenous progenitor cells, i.e., chemoprevention of etoposide-induced acute myelogenous leukemia.
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PMID:Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. 1046 37


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