Summary
DL-Buthionine-(S, R)-sulfoximine (BSO), a glutathione-depleting agent, was found to diminish the nephrotoxic effect of cisplatin (cis-diamminedichloroplatinum). Pretreatment of rats with BSO (4 mmol/kg s. c.) 2 h prior to cisplatin, either as a single dose of 5 mg/kg or at a daily dose of 2.5 mg/kg for 3 consecutive days, resulted in diminished elevations of plasma BUN concentration and decreased cisplatin-induced inhibition of renal γ-glutamylcysteine synthetase and γ-glutamyl transpeptidase activity measured 6 days following treatment. Administration of BSO prior to cisplatin at 7.5 mg/kg did not significantly alter the effect of cisplatin on either BUN concentration or enzyme activity. The influence of BSO pretreatment on the antitumor activity of cisplatin was studied using implantation of a murine bladder cancer (MBT-2) in C3H mice. Pretreatment of mice with BSO (5 mmol/kg) did not influence cisplatin antitumor efficacy.
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References
Cohn VH, Lyle J (1966) A fluorometric assay for glutathione. Anal Biochem 14: 434
Costa LG, Murphy SD (1986) Effect of diethylmaleate and other glutathione depletors on protein synthesis. Biochem Pharmacol 35: 3383
Doroshow JH, Locker GY, Baldinger J, Meyers CW (1979) The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 26: 285
Drew R, Miners JO (1984) The effects of buthionine sulfoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem Pharmacol 33: 2989
Galinsky RE (1986) Role of glutathione turnover in drug sulfation: differential effects of diethylmaleate and buthionine sulfoximine on the pharmacolinetics of acetaminophen in the rat. J Pharmacol Exp Ther 236: 133
Griffith OW, Meister A (1979) Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem 254: 7558
Hamilton TC, Winker MA, Louie KG, Batist G, Behrens BC, Tsuruo T, Grotzinger KR, McKoy WM, Young RC, Ozols RF (1985) Augmentation of adriamycin, melphalan and cisplatin cytotoxicity in drug-resistant and-sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol 34: 2583
Lee K, Weiss G, O'Donnell RW, Cockett ATK (1987) Reduction of bladder cancer growth in mice treated with intravesicalBacillus Calmette Guérin and systemic interleukin 2. J Urol 137: 1270
Leyland-Jones B, Morrow C, Tate S, Urmacher C, Gordon C, Young CW (1983)cis-Diamminedichloro platinum (II) nephrotoxicity and its relationship to renal γ-glutamyl transpeptidase and glutathione. Cancer Res 43: 6072
Litterst CL, Tong S, Hirokata Y, Siddik ZH (1982) Alteration in hepatic and renal levels of glutathione and activities of glutathioneS-transferases from rats treated with cis-dichlorodiammine platinum-II. Cancer Chemother Pharmacol 8: 67
Litterst CL, Bertolero F, Uozumi J (1986) The role of glutathione and metallothionein in the toxicity and subcellular binding of cisplatin: In McBrian DCH, Slater TF (eds) Biochemical mechanisms of platinum antitumor drugs. IRL Press, Oxford, p 227
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265
Maines MD (1986) Differential effect of cis-platinum on regulation of liver and kidney haem and haemoprotein metabolism. Biochem J 237: 713
Meister A (1985) The fall and rise of cellular glutathione levels: enzyme based approaches. Curr Top Cell Regul 26: 383
Meister A, Tate SS, Griffith OW (1981). γ-Glutamyl transpeptidase. Methods Enzymol 77: 237
Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB (1973) Acetaminophan-induced hepatic neprosis: IV. Protective role of glutathione. Pharmacol Exp Ther 187: 211
Pfeifle CE, Howell SB, Felthouse RD, Woliver TBS, Andrews PA, Markman M, Murphy MP (1985) High dose cisplatin with sodium thiosulfate protection. J Clin Oncol 3: 237
Schnellmann RG, Mandell LJ (1986) Multple effects of presumed glutathione depletors on rabbit proximal tubules. Kidney Int 29: 858
Sekura R, Meister A (1976) γ-Glutamylcysteine synthetase. J Biol Chem 252: 2599
Sun JD, Ragsdale SS, Benson JM, Henderson RF (1985) Effects of long-term depletion of reduced glutathione in mice administeredL-buthionine-S, R sulfoximine. Fund Appl Toxicol 5: 913
Taussky HH, Shorr E (1953) A microscopic method for the determination of inorganic phosphorus. J Biol Chem 202: 675
Tew KW, Woodworth A, Sterns ME (1986) Relationship of glutathione depletion and inhibition of glutathione-S-transferase activity to the antimitotic properties of estramustine. Cancer Treat Rep 70: 715
Tomashefsky P, Astor M, White RD (1985) Relationship between thiol depletion and chemosensitization in a transplantable murine bladder tumor. JNCI 74: 1233
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Mayer, R.D., Lee, Ke. & Cockett, A.T.K. Inhibition of cisplatin-induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor. Cancer Chemother. Pharmacol. 20, 207–210 (1987). https://doi.org/10.1007/BF00570486
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DOI: https://doi.org/10.1007/BF00570486