Antileukemic Effects of Buthionine Sulfoximine (BSO) (NSC 326231) in Vivo: A Pilot Study in Acute Myeloblastic Leukemia

Abstract

In this pilot study we have tested the in vivo effects of the potent glutathione (GSH)-depleting agent buthionine sulfoximine (BSO) on the peripheral blood blast cells of 6 patients with acute myeloblastic leukemia (AML) in relapse. The clinical trial was designed to extend the observation that in the presence of BSO the cells of some blast populations are depleted of GSH and undergo apoptosis. Each patient received a continuous intravenous infusion of BSO over 72 hours. A loading dose of 3 Gm/m2 body surface area (BSA) was given over 30 minutes followed by a continuous infusion at a rate of 0.75 Gm/m2 BSA/hour. Blood was drawn before the start of BSO, at 24,48 and 72 hours and later times after BSO to determine clonogenic cell recovery (CCR) and to measure by flow cytometry intracellular GSH and reactive oxygen intermediates (ROI). In vitro BSO dose responses were determined by exposing AML blast cells to a range of doses of BSO for 48 hours in suspension culture; cells were then washed, counted and an aliquot plated in methylcellu-lose to enable calculation of CCR. BSO levels were measured every 12 hours during the infusion of BSO. The AML continuous cell line OCI/AML-5 was used to determine the effect of BSO on resistance to cytosine arabinoside (ARA-C) in culture. For 5 patients CCR in vivo was measured serially; CCR for two patients decreased to <20% of control, for two patients to <70% and for one patient there was no change. Serial intracellular GSH values were available for 4 of these patients with reductions ranging from 32 to 45% of control. Plasma BSO levels showed patient to patient heterogeneity. Clinical status and blood counts remained stable during BSO; no significant toxicity was observed. The ARA-C resistance of OCI/AML-5 cells was reduced in the presence of BSO.