Glutathione and glutathione S-transferases in a human plasma cell line resistant to melphalan

Abstract

We report the development of a melphalan-resistant HS-Sultan human plasma cell line. The melphalan-resistant [MEL(R)] cell line was 16.7-fold more resistant to melphalan in vitro than the parent cell line [MEL(S)]. The wild type and MEL(R) HS-Sultan cell lines formed localized plasmacytomas when injected into nude mice. A dose-response effect of melphalan against the drug-sensitive plasmacytomas was present in vivo. A dose of 10 mg/kg of melphalan, which caused a 90% regression of MEL(S) plasmacytomas, had no effect on the MEL(R) plasmacytomas in vivo. In contrast to previous reports, there was no increase in the levels of glutathione (GSH) in the MEL(S) and MEL(R) plasmacytomas, suggesting that the association of elevated glutathione levels and melphalan resistance may not be common to all drug-resistant lines. In the MEL(R) plasmacytomas, there was a 1.5-fold induction of a pi type glutathione S-transferase (GST) as evidenced by isoelectric focusing (IEF) and Western blotting. This GST isoenzyme was purified and, although immunochemically similar to the pi type isoenzymes induced in other drug-resistant cell lines, was noted to have different functional characteristics. These data suggest that, depending on cell type and the drug studied, functionally different GST isoenzymes may be induced and they could be of importance in the development of drug resistance.