Rapid development of glutathione-S-transferase-dependent drug resistance in vitro and its prevention by ethacrynic acid.
Exposure of A2780 human ovarian tumor cells to a low concentration of melphalan in vitro for 7 days resulted in the development of melphalan resistance. This resistance was not a stable characteristic of the cells since it was lost after 2 weeks in culture in the absence of drug. The melphalan-resistant cells exhibited significant cross-resistance to cisplatin but only minor cross-resistance to doxorubicin. The resistant cells had elevated levels of glutathione-S-transferase activity and mRNA. Exposure of the cells to the ethacrynic acid resulted in a decrease in enzyme activity as well as a reversal of their drug-resistant phenotype, indicating that the enzyme is involved in the resistance. When ethacrynic acid was present during the 7-day exposure of the cells to melphalan, the development of drug resistance was prevented. This system may serve as a useful preliminary step in screening for agents which can prevent the development of chemotherapy-induced drug resistance in human cancer.
Caffrey
P B
PB
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Zhu
M
M
Zhang
Y
Y
Chinen
N
N
Frenkel
G D
GD
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology*; D015152:Blotting, Northern; D019008:Drug Resistance, Neoplasm; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005260:Female; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008558:Melphalan / Q000378:metabolism / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D005982:Glutathione Transferase; D004976:Ethacrynic Acid; D008558:Melphalan