Health & Environmental Research Online (HERO)


5:3 acid (914637-49-3)


142 References Were Found:

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

ENHANCEMENT OF DIFFERENTIATION AND CYTOTOXICITY OF LEUKEMIA-CELLS BY COMBINATIONS OF FLUORINATED PYRIMIDINES AND DIFFERENTIATION INDUCERS - DEVELOPMENT OF DNA DOUBLE-STRAND BREAKS

Authors: Waxman, S; Huang, Y; Scher, BM; Scher, M (1992) Biomedicine & Pharmacotherapy 46:183-192. HERO ID: 3860750

[Less] We have previously shown that pretreatment of mouse erythroleukemia (MEL) cells with the fluorinated . . . [More] We have previously shown that pretreatment of mouse erythroleukemia (MEL) cells with the fluorinated pyrimidines 5-fluorouracil (FUra) or 5-fluorodeoxyuridine (FUdR) followed by the differentiation inducer hexamethylene bisacetamide (HMBA) greatly enhanced the magnitude of their differentiation and caused extensive cell death. We have now extended these studies to address the mechanism that may be responsible for this enhancement and have also examined a human leukemic cell line (HL-60) for its sensitivity to this combination cytotoxic-differentiation therapy. We found that in HL-60 cells, pretreatment with FUdR, but not FUra, followed by 1.2% dimethylsulfoxide (DMSO) led to an 8 to 10-fold enhancement of cell death as compared to FUdR alone. When all-trans-retinoic acid (ATRA) was used instead of DMSO, the enhancement of differentiation and cytotoxicity was 5-fold. The percent of cells induced to differentiate was dependent on the concentration of both FUdR and ATRA. In HL-60 cells resistant to ATRA-induced differentiation. the combination of FUdR and ATRA did not result in enhanced cytotoxicity. Leucovorin (LV), a compound known to enhance the inhibitory effect of FUra or FUdR on DNA synthesis, increased the effectiveness of the cytotoxic-differentiation therapy, whereas thymidine inhibited its effectiveness. This suggests that inhibition of DNA metabolism may be an integral part of the differentiation-enhancing cytotoxic mechanism. To further explore inhibition of DNA synthesis, DNA was extracted under alkaline or neutral conditions from H-3-thymidine-labelled cells that were treated with FUra/LV and HMBA individually or in combination. The emergence of single and double-strand DNA breaks was monitored by agarose gel electrophoresis. In parallel to the enhancement of cytotoxicity, the combination treatment (FUra/LV followed by HMBA) also produced a 2.5-3-fold increase in the DNA breaks when compared to the same effect obtained by the agents applied individually. Thus, we propose that DNA degradation may be the mechanism responsible for the enhanced loss of cell viability. In summary, we report here an approach which is targeted to increasing the death rate of leukemic cells through the combined use of low doses of cytotoxic drugs and differentiation inducers.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Rat liver metabolism and toxicity of 2,2,2-trifluoroethanol

Authors: Kaminsky, LS; Fraser, JM; Seaman, M; Dunbar, D (1992) Biochemical Pharmacology 44:1829-1837. HERO ID: 1938179

[Less] 2,2,2-Trifluoroethanol (TFE) is a metabolite of anesthetic agents and chlorofluorocarbon alternatives. . . . [More] 2,2,2-Trifluoroethanol (TFE) is a metabolite of anesthetic agents and chlorofluorocarbon alternatives. Its toxicity in rats is a consequence of its metabolism to 2,2,2-trifluoroacetaldehyde (TFAld) and then to trifluoroacetic acid (TFAA). The enzymes involved in the toxic metabolic pathway have been investigated in this study. For the reaction of TFE to TFAld, the major hepatic metabolism associated with toxicity (as assessed by pyrazole-inhibitability) was NADPH dependent and occurred in the microsomes, whereas for TFAld conversion to TFAA, NADPH-dependent microsomal metabolism was significant, but mitochondrial and cytosolic metabolism in the presence of NADPH were also major contributors. NADPH-dependent hepatic microsomal metabolism of TFE to TFAld and TFAld to TFAA was inhibited by carbon monoxide, 2-allyl-2-isopropylacetamide, SKF-525A, metyrapone, imidazole, and pyrazole, and both reactions were oxygen dependent. The metabolism of TFE to TFAld was inhibited by diethyldithiocarbamate, a specific inhibitor of cytochrome P450E1, and by a monoclonal antibody to P4502E1, whereas the metabolism of TFAld was inhibited by neither. Ethanol pretreatment of rats enhanced the Vmax for hepatic microsomal metabolism of TFE to TFAld from 5.3 to 9.7 nmol/mg protein/min, while for TFAld to TFAA the Vmax was increased from 4.3 to 6.5 and the Km was unaffected for both reactions. Phenobarbital pretreatment of the rats did not affect any of these kinetic parameters. Coadministration of ethanol and a lethal dose of TFE very markedly decreased the lethality. Both the lethality (LD50 0.21 to 0.44 g/kg) and the metabolic kinetic parameters [(Vmax/Km)H(Vmax/Km)D = 4.2] were affected markedly when deuterated TFE replaced TFE. In contrast, deuteration of TFAld did not affect its lethality or rates of metabolism, but did affect its Km. Taken together these results indicate that P4502E1 catalyzed toxicity-associated hepatic metabolism of TFE to TFAld, while TFAld metabolism was catalyzed by a P450 which was not P4502E1. The hepatic metabolism of TFAld was not associated with its toxicity, which has been determined previously to be associated with its intestinal metabolism.