Summary
Male Sprague Dawley rats were treated with buthionine sulfoximine (BSO) and cisplatin in different doses and schedules to optimize the chemoprotective effect of BSO against cisplatin nephrotoxicity. BSO at 4 mmol/kg, administered s.c. 2 h prior to cisplatin, resulted in normal blood urea nitrogen (BUN) levels in rats treated with 3 or 4 mg/kg cisplatin, and modestly, but significantly reduced the toxicity of cisplatin at 5 mg/kg. Administration of BSO (4 mmol/kg) at intervals ranging from 0 to 16 h prior to cisplatin (5 mg/kg) resulted in a significant reduction in BUN values. A BSO dose as low as 0.04 mmol/kg was found to be as effective as 4 mmol/kg against nephrotoxicity associated with cisplatin at 4 mg/kg. Repetitive injections of BSO (1 mmol/kg every 12 h, four times, beginning 2 h prior to cisplatin) significantly inhibited elevations of BUN associated with high-dose cisplatin (6 mg/kg), whereas a single BSO injection of 4 mmol/kg was ineffective. The degree and duration of renal glutathione depletion was related to the dose of BSO. Renal glutathione content following 4 mmol/kg BSO was 38% of control at 2 h and 40% at 24 h; following 0.04 mg/kg, glutathione was 47% at 2 h and almost 100% at 24 h. Simultaneous in vitro administration of BSO did not inactivate cisplatin cytotoxicity as measured by the colony-forming ability of MBT-2 cells in soft agar. These data indicate that repeated injections of BSO, beginning prior to cisplatin administration, would improve the nephroprotective effect without compromising the chemotherapeutic efficacy of cisplatin. It is suggested that the ability of BSO to reduce cisplatin nephrotoxicity may not correlate with the degree of renal glutathione depletion and that the mechanism of action is unlikely to involve direct inactivation of cisplatin.
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Abbreviations
- BSO:
-
δλ-buthionine sulfoximine
- BUN:
-
blood urea nitrogen
References
Borch RF, Katz JC, Lieder PH, Pleasants ME (1980) Effect of diethyldithiocarbamate rescue on tumor response to cisplatinum in a rat model. Proc Natl Acad Sci USA 77:5441–5444
Cohn VH, Lyle J (1966) A flurometric assay for glutathione. Anal Biochem 14:434–440
Griffeth OW (1982) Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 257:13704–12
Griffeth OW, Bridges RJ, Meister A (1979) Transport of gamma glutamyl (amino acids). Role of glutathione and gamma glutamyl transpeptidase. Proc Natl Acad Sci USA 76:6319–6322
Howell SB, Pfeifle CL, Wung WE, Olsheu RA, Lucas WE, You JL, Green M (1982) Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 97:845–851
Lee K, Weiss G, O'Donnell RW, Cockett ATK (1987) Reduction of bladder cancer growth in mice treated with intravesical Bacillus Calmette Guerin and systemic interleukin 2. J Urol 137:1270–73
Lee K, Mayer RD, Cockett ATK (1989) Effect of systemic glutathione depletion by buthionine sulfoximine on the sensitivity of murine bladder cancer to cytotoxic agents. Urology (in press)
Lee K, Smith P, Weiss GH, Cockett ATK (1989) Clonal growth of bladder cancer cells in double layer soft agar assay: needless addition of multiple culture supplements. Urol Res (in press)
Litterst CL (1981) Alterations in the toxicity of cisdichlorodiammine platinum and in tissue localization of platinum as a function of NaCl concentration in the vehicle of administration. Toxicol Appl Pharmacol 61:99–108
Mayer RD, Lee K, Cockett ATK (1987) Inhibition of cisplatin-induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor. Cancer Chem Pharmacol 20:207–10
Meister A (1985) The fall and rise of cellular glutathione levels: enzyme based approaches. Curr Top Cell Regul 26:383–94
Naganuma A, Satoh M, Imura M (1987) Prevention of lethal and renal toxicity of cis-diamininedichloroplatinum (II) by induction of metallothione in synthesis without compromising its antitumor activity in mice. Cancer Res 47:983–87
Rosenberg B (1985) Fundamental studies with cisplatinum. Cancer 55:2303–2316
Safirstein R, Winston J, Goldstein M, Moel D, Dikman S, Guttenplan J (1986) Cisplatin Nephrotoxicity. Am J Kid Dis 8(5):356–367
Salmon SE (1984) Human tumor colony assay and chemosensitivity testing. Cancer Treat Rep 68:117–125
Schuellmann RG, Mandell LJ (1986) Multiple effects of presumed glutathione depletors on rabbit proximal tubules. Kidney Int 29:858–62
Soehnlen B, Young L, Liu R (1980) Standard laboratory procedures for in vitro assay of human tumor stem cells. In: Salmon SE (ed) Cloning of human tumor stem cells. Liss, New York, pp 331–34
Soloway MS (1977) Intravesical and systemic chemotherapy of murine bladder cancer. Cancer Res 37:2918–2929
Yuhas JM, Culo F (1980) Selective inhibition of the nephrotoxicity of cis-dichlorodiammine platinum (II) by WR-2721 without altering its antitumor properties. Can Treat Rep 64:57–64
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Mayer, R.D., Lee, Ke. & Cockett, A.T. Improved use of buthionine sulfoximine to prevent cisplatin nephrotoxicity in rats. J Cancer Res Clin Oncol 115, 418–422 (1989). https://doi.org/10.1007/BF00393329
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DOI: https://doi.org/10.1007/BF00393329