Rapid development of glutathione-S-transferase-dependent drug resistance in vitro and its prevention by ethacrynic acid

Cancer Lett. 1999 Feb 8;136(1):47-52. doi: 10.1016/s0304-3835(98)00307-3.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Alkylating / metabolism
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Blotting, Northern
  • Drug Resistance, Neoplasm*
  • Ethacrynic Acid / pharmacology*
  • Female
  • Glutathione Transferase / antagonists & inhibitors*
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Melphalan / metabolism
  • Melphalan / pharmacology*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology*
  • RNA, Messenger
  • RNA, Neoplasm
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Alkylating
  • RNA, Messenger
  • RNA, Neoplasm
  • Glutathione Transferase
  • Ethacrynic Acid
  • Melphalan