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)

Through the use of drug-adapted tissue culture cells, correlations have been observed between the level of specific enzymes and drug resistance. Drug resistance, however, may be due to multiple factors. To test whether the activity of daunorubicin reductase or NADPH diaphorase independently influences in vitro daunorubicin-induced cytotoxicity, we developed somatic cell hybrid clones to partially isolate these factors. This was accomplished by fusing daunorubicin-resistant myeloblast cells obtained from a patient with monosomy 7 leukemia to a daunorubicin-sensitive Chinese hamster cell line. The in vitro cytotoxicity of daunorubicin was compared in hybrid clones having variable enzyme activities; the concentrations of daunorubicin that inhibited the growth of clones by 50% did not differ by more than 2-fold, whereas daunorubicin reductase activities and NADPH diaphorase isozyme activities differed by more than 100- and 15-fold, respectively. These large differences in enzymatic activity were obtained in part by the suppression of specific hamster genes, indicating a regulatory control mechanism for xenobiotic enzymes. Our findings suggest that in this system substantial intercellular variation in the activity of these xenobiotic enzymes does not independently influence cellular resistance to daunorubicin.
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PMID:Use of somatic cell hybrids to analyze role of specific enzymes in daunorubicin cytotoxicity. 354 57

The role of lipid peroxidation, intracellular glutathione and Ca2+ concentration in menadione-mediated toxicity was investigated in human hepatoma cell lines, Hep G2 and Hep 3B, and in human leukemia cell lines, CCRF-CEM and MOLT-3. Incubation of these cells with 80 microM menadione at 37 degrees C resulted in depletion of intracellular glutathione, increased intracellular Ca2+, and increased lipid peroxidation, events leading to cell degeneration. The sensitivity of these cells to menadione, in order, was: Hep G2 cells > Hep 3B cells > CCRF-CEM cells and MOLT-3 cells. The extent of menadione-induced lipid peroxidation in different cell types followed the same order as did their susceptibility to menadione-induced cell degeneration. The menadione-induced depletion in glutathione level was in the following sequence: Hep G2 cells > MOLT-3 and CCRF-CEM cells > Hep 3B cells. The extent of the menadione-induced increase in the intracellular Ca2+ concentration was: Hep G2 cells > Molt-3 cells > CCRF-CEM cells and Hep 3B cells. Pre-treatment of Hep G2 cells with 20 mM deferoxamine mesylate, an iron chelator, reduced both the menadione-induced cell degeneration and lipid peroxidation; however, it did not prevent the menadione-induced increase in intracellular Ca2+ nor the depletion of glutathione. These data suggest that menadione-induced cell degeneration is directly linked to lipid peroxidation, and that it is less related to the rise in intracellular Ca2+ and the depletion in glutathione content. Dicumarol (an inhibitor of DT diaphorase) enhanced the capacity of menadione to induce Hep 3B cell degeneration from 71.3% to 86.2% after 120 min of menadione treatment at 37 degrees C, but did not have this effect in Hep G2, CCRF-CEM or MOLT-3 cells. The activities of DT diaphorase were 52.4, 39.6, 1.5 and 1.8 nmol cytochrome c reduced/min/mg protein in Hep G2, Hep 3B, CCRF-CEM and MOLT-3 cells, respectively. The activity of DT diaphorase was much higher in Hep G2 cells than in the other cells. It seems that DT diaphorase may not, as suggested by others, protect against cell degeneration by quinones, such as menadione.
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PMID:Menadione-induced cell degeneration is related to lipid peroxidation in human cancer cells. 953 16