ACTIVITY OF MELPHALAN IN COMBINATION WITH THE GLUTATHIONE TRANSFERASEINHIBITOR SULFASALAZINE

Glutathione (GSH) transferases (GST), a family of detoxification enzym e proteins, are suggested to play an important role in tumor cell resi stance to melphalan. The GST-activity inhibitor ethacrynic acid has be en shown to increase the antitumor activity of melphaln in vitro as we ll as in vivo. In this study we determined the activity and toxicity o f melphalan in combination with another GST-activity inhibitor, sulfas alazine, an agent used to treat ulcerative colitis. We entered 37 prev iously treated patients with advanced cancer of different histologies on sulfasalazine given at the individually calculated maximum tolerate d dose (MTD) and melphalan given at doses beginning at 20 mg/m(2). The main toxicity arising from this combination was nausea and vomiting, whereas increased myelosuppression was not observed. A partial respons e was seen in 2/4 of the ovarian cancer patients only. Plasma sulfasal azine levels varied between 2.5 and 47.1 mu g/ml. Although reductions in GSH/GST levels were observed in peripheral mononuclear cells of cer tain patients following sulfasalazine treatment, there was no correlat ion between the extent of reduction and the plasma sulfasalazine level . A larger patient population must be studied to determine the usefuln ess of this combination.