Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to modulate nitrosourea resistance in breast cancer

Biochem Pharmacol. 1994 Aug 3;48(3):543-8. doi: 10.1016/0006-2952(94)90284-4.

Abstract

MCF-7 human breast cancer cells possess high levels of O6-alkylguanine-DNA alkyltransferase and moderate levels of glutathione, and are more resistant to chloroethylnitrosoureas (CNUs) than cells with low levels of either molecule. The role of each as a component of CNU resistance was assessed using O6-benzylguanine (O6-bG) or O6-methylguanine (O6-mG) to deplete the alkyltransferase and L-buthionine sulfoxamine (L-BSO) to deplete glutathione. O6-bG and O6-mG potentiated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, resulting in a dose modification factor of 5.4 and 2.3, respectively, which reflected the more potent inhibitory effect of O6-bG. L-BSO alone had little effect on the survival of MCF-7 cells following BCNU exposure, but when combined with O6-mG, BCNU cytotoxicity was additive, yielding a dose modification factor of 3.2. O6-bG or O6-mG and L-BSO acted independently, as neither class of inhibitor affected the other's mechanism of CNU resistance. Furthermore, MCF-7 cells overexpressing GST mu were not more resistant to BCNU than the parent cell line in either the presence or absence of O6-bG or L-BSO. These results indicate that on a relative basis in MCF-7 cells, the alkyltransferase is the cell's first line of defense against CNUs. This suggests that therapeutic trials based on O6-bG-induced biochemical modulation of CNU resistance may increase the efficacy of these chemotherapeutic agents against human malignant cells and that L-BSO may have little additive effect when used with these agents.

Publication types

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

MeSH terms

  • Breast Neoplasms / metabolism*
  • Carmustine / pharmacology
  • Cell Line
  • Cell Survival
  • Drug Resistance
  • Ethylnitrosourea / analogs & derivatives*
  • Ethylnitrosourea / pharmacology
  • Glutathione / antagonists & inhibitors*
  • Glutathione Transferase / analysis
  • Guanine / analogs & derivatives
  • Guanine / pharmacology
  • Humans
  • Methyltransferases / antagonists & inhibitors*
  • O(6)-Methylguanine-DNA Methyltransferase

Substances

  • O(6)-benzylguanine
  • 1-(2-chloroethyl)-1-nitrosourea
  • Guanine
  • O-(6)-methylguanine
  • Methyltransferases
  • O(6)-Methylguanine-DNA Methyltransferase
  • Glutathione Transferase
  • Glutathione
  • Ethylnitrosourea
  • Carmustine