Possible Role of Inhibition of Glutathione »S-Transferase in the Partial Reversal of Chlorambucil Resistance by Indomethacin in a Chinese Hamster Ovary Cell Line1

We have reported previously the isolation and characterization of a Chinese hamster ovary cell line, designated CHO-Chl1, which exhibits resistance to bifunctional nitrogen mustards while maintaining sensitivity to a range of other alkylating agents and chemotherapeutic drugs. This enhanced drug resistance is associated with a greater than 40-fold in crease in the level of expression of an alpha class (YcYc) glutathione .Vtransferase (GST) as compared to the parental, CHO-K1, cell line. Here, we have purified GST from CHO-Chlr cells and show that the nonsteroidal am ¡inflammatorydrug indomethacin acts as an inhibitor of enzyme activity. Indomethacin at 500 /IMcauses no significant decrease in colony forming ability of either CHO-K1 or CHO-Chl' cells. However, the cytotoxicity of chlorambucil is potentiated 5.5-fold in CHO-Chlr cells, but only 2.5-fold in CHO-K1 cells following preexposure to 500 ¿IM indomethacin. In contrast, the antiinflammatory agent acetylsalicylic acid failed to inhibit the activity of purified GST and caused no potentiation of chlorambucil toxicity, suggesting that the potentiation by indomethacin is not due to the effects of this drug on prostaglandin synthesis. These studies provide further evidence that GSTs may be involved in the development of resistance to bifunctional alkylating agents and suggest that indomethacin, or agents with similar activities, may be of value as an adjunct to chemotherapy in some patients with tumors resistant to treatment with alkylating agents.