Clinical Cancer Research, Vol 2, Issue 12 1961-1968, Copyright © 1996 by American Association for Cancer Research

ARTICLES

d,l-buthionine-(S,R)-sulfoximine potentiates in vivo the therapeutic efficacy of doxorubicin against multidrug resistance protein-expressing tumors

U Vanhoefer, S Cao, H Minderman, K Toth, BS Skenderis 2nd, ML Slovak and YM Rustum
Department of Experimental Therapeutics, Grace Cancer Drug Center and Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Intracellular glutathione (GSH) has been implicated as a regulatory determinant of multidrug resistance protein (MRP) function. The objective of the present study was to evaluate in vivo the ability of d,l-buthionine-(S,R)-sulfoximine (d,l-BSO), a potent inhibitor of GSH biosynthesis, to reverse MRP-mediated drug resistance to doxorubicin. Athymic nude mice (nu/nu) bearing advanced parental human fibrosarcoma HT1080 and MRP-expressing HT1080/DR4 tumors were treated with the maximum tolerated dose of doxorubicin (10 mg/kg, i. v. push). This therapy produced an overall response rate of 50% (20% complete response and 30% partial response) in mice bearing parental HT1080 xenografts, whereas no significant antitumor activity against HT1080/DR4 tumors was observed. Treatment of mice bearing HT1080 and HT1080/DR4 xenografts with a continuous i.v. infusion of nontoxic doses of d,l-BSO (300 and 600 mg/kg/day) produced a 60% reduction of GSH plasma levels and greater than 95% reduction in GSH tumor levels in both parental and multidrug-resistant tumors; however, this treatment possessed no in vivo antitumor activity by itself. Under these treatment conditions, a combination of d,l-BSO with the maximum tolerated dose of doxorubicin administered at 24 h during a 48-h i.v. infusion of d,l-BSO completely restored the response of MRP-expressing HT1080/DR4 tumors to doxorubicin (overall response rate, 63%; complete response rate, 38%) with no potentiation of host toxicity. The d,l-BSO-induced in vivo reversal of MRP-mediated drug resistance correlated in vitro with the restoration of intracellular doxorubicin retention in cultured HT1080/DR4 cells. Depletion of GSH by d,l-BSO in drug-sensitive HT1080 tumors that do not express MRP did not alter the in vivo response to doxorubicin. Using the same treatment schedule, dose, and administration of doxorubicin with and without d,l-BSO in nude mice bearing P-170 glycoprotein-expressing A2780/Dx5 tumors, no potentiation of the therapeutic index of doxorubicin was found, demonstrating the in vivo selectivity of d, l-BSO-induced GSH depletion on MRP-function. The data reported herein indicate that in vivo function of MRP as a mediator of doxorubicin resistance requires the presence of sufficient GSH pools. d,l-BSO may provide an example of an effective in vivo modulator of MRP-mediated drug resistance.

This article has been cited by other articles:

				R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]

				M. Faundez, L. Pino, P. Letelier, C. Ortiz, R. Lopez, C. Seguel, J. Ferreira, M. Pavani, A. Morello, and J. D. Maya Buthionine Sulfoximine Increases the Toxicity of Nifurtimox and Benznidazole to Trypanosoma cruzi Antimicrob. Agents Chemother., January 1, 2005; 49(1): 126 - 130. [Abstract] [Full Text] [PDF]

				Q. Mao, W. Qiu, K. E. Weigl, P. A. Lander, L. B. Tabas, R. L. Shepard, A. H. Dantzig, R. G. Deeley, and S. P. C. Cole GSH-dependent Photolabeling of Multidrug Resistance Protein MRP1 (ABCC1) by [125I]LY475776. EVIDENCE OF A MAJOR BINDING SITE IN THE COOH-PROXIMAL MEMBRANE SPANNING DOMAIN J. Biol. Chem., August 2, 2002; 277(32): 28690 - 28699. [Abstract] [Full Text] [PDF]

				J. Liu, H. Chen, D. S. Miller, J. E. Saavedra, L. K. Keefer, D. R. Johnson, C. D. Klaassen, and M. P. Waalkes Overexpression of Glutathione S-Transferase II and Multidrug Resistance Transport Proteins Is Associated with Acquired Tolerance to Inorganic Arsenic Mol. Pharmacol., August 1, 2001; 60(2): 302 - 309. [Abstract] [Full Text] [PDF]

				L. Pendyala, P. J. Creaven, G. Schwartz, N. J. Meropol, W. Bolanowska-Higdon, J. Zdanowicz, M. Murphy, and R. Perez Intravenous Ifosfamide/Mesna Is Associated with Depletion of Plasma Thiols without Depletion of Leukocyte Glutathione Clin. Cancer Res., April 1, 2000; 6(4): 1314 - 1321. [Abstract] [Full Text]

				K. Toth, M. M. Vaughan, G. Schwartz, J. S. Winston, B. S. Skenderis II, H. K. Slocum, and Y. M. Rustum Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections International Journal of Surgical Pathology, July 1, 1998; 6(3): 145 - 154. [Abstract] [PDF]