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Ruscoe Julie , O'Brien Miechelle , Freer Seema , Shen Hongxie , Rosario Lilliam , Vulevic Bojana , Tew Kenneth D
Co-ordinate expression of detoxification genes in drug resistance
Clinical Chemistry and Enzymology Communications. 2000 ;8(4-6) :403-416
PMID: AN 2000:257176   
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Abstract
A review, with 34 refs. The acquisition of drug resistance in cancer therapy is multifactorial, often involving genes from the same cellular pathway. This is exemplified in a leukemic cell line (HL60) studied for the development of drug resistance to two unrelated drugs, g-glutamyl-S-(benzyl)cysteinyl-R-(-)-Ph glycine di-Et ester, an analog of glutathione and adriamycin (ADR), a DNA-damaging agent. Multiple genes from the glutathione detoxification pathway are upregulated. These include g-glutamyl cysteine synthetase, the glutathione-S-transferase isoenzyme P1-1, and the multidrug resistance-assocd. protein (MRP1). Concurrent with elevations in these proteins was a decrease in intracellular glutathione, which may be a reflection of increased MRP1-mediated efflux. DNA-dependent protein kinase and its assocd. Ku 70 autoantigen were also overexpressed in HL60/ADR cells, resulting in an increased DNA repair and kinase activity. The kinase activity was inhibited by an azidophenacyl glutathione conjugate, and may be a consequence of destabilization of the holoenzyme. Results suggest the importance of detoxification mechanisms in the response of the cell to chem. induced stress, in particular those of the glutathione pathway. [on SciFinder (R)]
Notes
CAN 133:162250 14-0 Mammalian Pathological Biochemistry Department of Pharmacology,Fox Chase Cancer Center,Philadelphia,PA,USA. Journal; General Review 0892-2187 written in English. 9026-43-1 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), BIOL (Biological study) (DNA-dependent; coordinate expression of glutathione detoxification genes in cancer drug resistance); 25316-40-9 (Adriamycin); 168682-53-9 Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), THU (Therapeutic use), BIOL (Biological study), USES (Uses) (coordinate expression of glutathione detoxification genes in cancer drug resistance); 9023-64-7 (g-Glutamyl cysteine synthetase); 50812-37-8 (Glutathione-s-transferase) Role: BSU (Biological study, unclassified), BIOL (Biological study) (gene; coordinate expression of glutathione detoxification genes in cancer drug resistance)