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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Mayer RJ, Davis RB, Schiffer CA, Berg BL, Schuman P, Omura GA, Moore JO, Mclntyre OR. Frei 3rd E. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994, 31:896–903.
Bishop JF, Mathews JP, Young GA, Szar J, Gillet A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996, 87:1710–7.
Mitus AJ, Miller RB, Schenkein DP, Ryan HF, Parsons SK, Wheeeler C, Antin JH. Improved survival for patients with acute myelogenous leukemia. J Clin Oncol 1995,13:560–9.
Cassileth PA, Harrington DP, Appelbaum FR, Hillard M, Lazarus MD, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998,339:1649–56.
Hedley DW, McCulloch EA. Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. Leukemia 1996,10:1143–49.
Hedley DW, McCulloch EA, Minden MD, Chow S, Curtis JE. Antileukemic action of buthionine sulfoximine: evidence for an intrinsic death mechanism based on oxidative stress. Leukemia 1998, 12:1545–52.
Hu Z-B, Minden MD, McCulloch EA. Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the cytosine arabinoside sensitivity of leukemic stem cells. Leukemia 1995, 9:1667–73.
Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmac Ther 1991, 51:155–194.
Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994, 54:4313–20.
O’Dwyer PJ, Hamilton TC, Young RC, LaCreta FP, Carp N, Tew KD, Padavic K, Comis RL, Ozols RF. Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results. J Natl Cancer Inst 1992,84:264–67.
Bailey HH, Mulcahy RT, Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB, Wilding G, Pomplun M, Spriggs DR. Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an attempt at modulation of glurathione. J Clin Oncol 1994,12:194–204.
O’Dwyer PJ, Hamilton TC, LaCreta FP, Gallo JM, Kilpatrick D, Halbherr T, Brennan J, Bookman MA, Hoffman J, Young RC, Comis RL, Ozols RF. Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J Clin Oncol 1996,14:249–56.
Siemann DW, Beyers KL. In vivo therapeutic potential of combination thiol depletion and alkylating chemotherapy. Br J Haematol 1993,68:1071–79.
Zaman GJR, Lankelma J, van Tellingen O, Beijnen J, Dekker H, Paulusma C, Oude Elferink RPJ, Baas F, Borst. Role of glutathione in the export of compounds from cells by the multidrug-resistanceassociated protein. Proc Natl Acad Sci USA 1995, 92:6790–4.
Goddard P, Valenti M, Kelland LR. The role of glutathione (GSH) in determining sensitivity to platinum drugs in vivo in platinum-sensitive and-resistant leukaemia and plasmacytoma and human ovarian carcinoma xenografts. Anticancer Res 1994,14:1065–70.
Bain BJ. Leukaemia Diagnosis 2nd ed. Oxford, UK, Blackwell Science 1999.
Minden MD, Buick RN, McCulloch EA. Separation of blast cell and T-lymphocyte progenitors in the blood of patients with acute myeloblastic leukemia. Blood 1979,54:186–95.
Buick RN, Till JE, McCulloch EA. Colony assay for proliferating blast cells circulating in myeloblastic leukemia. Lancet 1977,1:862–3.
Nara N, McCulloch EA. The proliferation in suspension of the progenitors of the blast cells in acute myeloblastic leukemia. Blood 1985,65:1484–93.
Hoang T, McCulloch EA. Production of leukemic blast cell growth factor by a human bladder carcinoma cell line. Blood 1985,66:745–51.
Curtis JE, Minden MD, Minkin S, and McCulloch EA. A Comparison of the Sensitivities of AML Blast Stem Cells to Idarubicin and Daunorubicin. Leukemia. 1995,9: 396–404.
Curtis JE, Minkin S, Minden MD and McCulloch EA. A Role for Paclitaxel in the Combination Chemotherapy of Acute Myeloblastic Leukemia: Preclinical Cell Culture Studies. 1996, Br J Haematol, 95: 354–363.
Chow S, Hedley DW. Flow cytometric measurement of glutathione in clinical samples. Cytometry 1995,21:68–71.
Koyama H, Sugioka N, Hirata I, Ohta T, Kishimoto H. Determination of L-buthionin (SR)-sulfoximine, gamma-glutamylcysteine synthetase inhibitor in rat plasma with HPLC after prelabeling with dansyl chloride. J Chromatogr Sci 1996;34:326–9.
Curtis JE. Unpublished observations.
Meister A. Glutathione, ascorbate, and cellular protection. Cancer Res (suppl) 1994,1969s-1975s.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2001 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Curtis, J., Hedley, D.W., Minden, M.D., Moore, M.A., Mcculloch, E.A. (2001). Antileukemic Effects of Buthionine Sulfoximine (BSO) (NSC 326231) in Vivo: A Pilot Study in Acute Myeloblastic Leukemia. In: Büchner, T., Hiddemann, W., Wörmann, B., Schellong, G., Ritter, J., Creutzig, U. (eds) Acute Leukemias VIII. Haematology and Blood Transfusion / Hämatologie und Bluttransfusion, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18156-6_44
Download citation
DOI: https://doi.org/10.1007/978-3-642-18156-6_44
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-62109-3
Online ISBN: 978-3-642-18156-6
eBook Packages: Springer Book Archive