Summary
Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.
Similar content being viewed by others
References
Brock N, Pohl J (1983) The development of mesna for regional detoxification. Cancer Treat Rev 10 (Suppl A):33–43
Brock N, Pohl J, Stekar J, Scheef W (1982) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention. III. Profile of action of sodium 2-mercapto-ethane sulfonate (Mesna). Eur J Cancer Clin Oncol 18:1377–1387
Ehninger G, Rückle H, Haag C, Wilms K (1985) Die Therapie der Peritonealkarzinose mit intraperitonealer Gabe von cis-Diamino-dichloroplatin und systemischer Natriumthiosulfatprotektion. Onkologie 8:202–206
Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemother Pharmacol 50:219–245
Hofmann M, Wenzel M (1987) Verminderte Toxizität von Cisplatin durch Thioharnstoff und Sulfanilthiocarbamid. Tumor Diagn Ther 8:199–203
Howell SB, Taetle R (1980) Effect of sodium thiosulfate on cis-dichlorodiammine platinum (II): Toxicity and antitumor activity in L 1210 leukemia. Cancer Treat Rep 64:611–616
Howell SB, Pfeifle CL, Wang WE, Olshen RA, Lucas WE, You JL, Gree M (1982) Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med 97:845–851
Howell SB, Pfeifle CE, Wung WE, Olshen RA (1983) Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 43:1426–1431
Inouye S, Niizato T, Takeda U, Koeda T (1982) Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin. J Pharmacobiodyn 5:659–669
Ishizawa M, Taniguehi S, Baba T (1981) Protection by sodium thiosulfate and thiourea against lethal toxicity of cis-diamminechloroplatinum (II) in bacteria and mice. Jpn J Pharmacol 31:883–889
Iwamoto Y, Kawano T, Ishizawa M, Roki K, Kuroiwa T, Baba T (1985) Inactivation of cis-diamminedichloroplatinum in blood and protection of its toxicity by sodium thiosulfate in rabbits. Cancer Chemother Pharmacol 15:228–232
Kempf SR, Ivankovic S, Wiessler M, Schmähl D (1985) Effective prevention of the nephrotoxicity of cisplatin (CDDP) by administration of sodium 2-mercaptoethane-sulfonate (Mesna) in rats. Br J Cancer 52:937–939
Kreft B, Marre R, Schulz E, Sack K (1987) Experimentelle Untersuchungen zur nephroprotektiven Wirkung von Fosfomycin. Wien Med Wochenschr 4:83–88
Kumano N, Koinumaru S, Oizumi K, Konno K (1986) cis-Diamminedichloroplatinum (CDDP)-fosfomycin (FOM) combination in lung cancer patients with respect to the peripheral T-lymphocyte subsets. Tohoku J Exp Med 148:333–334
Kurebe M, Niizato T, Sanda M, Sasaki H, Hayasaka H (1985) Preventive effect of fosfomycin on the renal toxicity of cisplatin. Jpn J Antibiot 38:62–68
Litchfield JT Jr, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol 95:99–113
Miller BD, Siddik ZH, Millar JL, Jinks S (1985) Mesna does not reduce cisplatin-induced nephrotoxicity in the rat. Cancer Chemother Pharmacol 15:307–309
Neumann M (1983) Protective effect of fosfomycin on the nephrotoxicity of amikacin. In: Spitzy K (ed) Proceedings 13th international congress of chemotherapy, TOM 5/37, Egermann, Vienna, pp 14–19
Ohtani I, Ohtsuki K, Aikawa T, Sato Y, Anzai T, Ouchi J, Saito T (1984) Reduction of cisplatin toxicity by fosfomycin in animal models. Jpn J Cancer Chemother 11:2400–2407
Ormstad K, Orrenius S, Lastbom T, Uehara N, Pohl J, Stekar J, Brock N (1983) Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res 43:333–338
Sack K, Schulz E, Marre R, Kreft B (1987) Fosfomycin protects against tubulotoxicity induced by cis-diaminedichloroplatin and cyclosporin-A in the rat. Klin Wochenschr 65:525–527
Sauter C, Cogoli M, Arrenbrecht S, Marti C (1984) Neutralization of cis-dichlorodiammineplatinum II and nitrogen mustard by thiols. Recent Results Cancer Res 94:232–236
Talke H, Schubert GE (1985) Enzymatische Harnstoffbestimmung in Blut und Serum im optischen Test nach WARBURG. Klin Wochenschr 43:174–175
Author information
Authors and Affiliations
Additional information
Submitted in partial for the fulfilment of the requirements for the M. D. degree
Rights and permissions
About this article
Cite this article
Wagner, T., Kreft, B., Bohlmann, G. et al. Effects of fosfomycin, mesna, and sodium thiosulfate on the toxicity and antitumor activity of cisplatin. J Cancer Res Clin Oncol 114, 497–501 (1988). https://doi.org/10.1007/BF00391499
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00391499