Summary
An examination of the comparative nephrotoxicity in the tat of cisplatin, its hydrolysis product (mostlycis-[Pt(NH3)2Cl(H2O)]+ under the conditions applied), andcis-[Pt(NH3)2(guanosine)2]2+ revealed that these compounds differed significantly in the extent of renal damage they produced following their i.v. injection in Sprague-Dawley rats. The hydrolysis product was found to be the most toxic of the three complexes studied and produced nephrotoxicity at doses lower than those at which cisplatin was nephrotoxic. Under the conditions used, the i.v. administration ofcis-[Pt(NH3)2(guanosine)2]2+ resulted in no observable signs of nephrotoxicity at levels at which an equimolar dose of cisplatin produces clear evidence of renal function impairment and morphological alterations. The nephrotoxicity of these complexes appears to be generally related to the ease with which they undergo nucleophilic substitution reactions. The lack of substantial nephrotoxicity found forcis-[Pt(NH3)2(guanosine)2]2+ suggests that the products resulting from the action of the DNA repair processes on platinated DNA do not contribute significantly to the nephrotoxicity of cisplatin. Renal platinum levels found following the administration of these compounds correlated with the degree of nephrotoxicity produced by each compound, but no general correlation of nephrotoxicity and renal platinum levels was found. The nephrotoxicity ofcis-[Pt(NH3)2Cl(H2O)]2+ on a molar basis was estimated to be approximately 3 times as great as that of cisplatin itself.
Similar content being viewed by others
References
Daley-Yates PT, McBrien, DCH (1982) The inhibition of renal ATPase by cisplatin and some biotransformation products. Chem Biol Interact 40:325
Daley-Yates PT, McBrien DCH (1984) Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumor activity of cisplatin. Biochem Pharmacol 33:3063
Daley-Yates PT, McBrien DCH (1985) A study of the protective effect of chloride salts on cisplatin nephrotoxicity. Biochem Pharmacol 34:2363
Dobyan DC, Levi J, Jacobs C, Kosek J, Weiner MW (1980) Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations. J Pharmacol Exp Ther 213:551
Goren MP, Wright RK, Horowitz ME (1986) Cumulative renal tubular damage associated with cisplatin nephrotoxicity. Cancer Chemother Pharmacol 18:69
Groth S, Nielsen H, Sørensen JB, Christensen AB, Pedersen AG, Rørth M (1986) Acute and long-term nephrotoxicity of cis-platinum in man. Cancer Chemother Pharmacol 17:191
Hamilton CR, Bliss JM, Horwich A (1989) The late effects of cis-platinum on renal function. Eur J Cancer Clin Oncol 25:185
Jones MM, Beaty JA (1991) Rate of displacement of guanosine by cyanide fromcis-diamminebis(guanosine)platinum(II) chloride determined by using [13C]-NMR spectroscopy. Inorg Chem 30:1584
Jones TW, Chopra S, Kaufman JS, Flamenbaum W, Trump BF (1985)cis-Diamminedichloroplatinum(II)-induced acute renal failure in the rat. Lab Invest 52:363
Lim MC, Martin RB (1976) The nature ofcis-amine-Pt(II) and antitumorcis-amine-Pt(II) complexes in aqueous solutions. J Inorg Nucl Chem 38:1911
Lippert B (1988) Modelling platinum-nucleic acid interactions: coordination chemistry with biological aspects. Gazz Chim Ital 118: 153
Litterst CL (1981) Alterations in the toxicity ofcis-dichlorodiammineplatinum(II) and in tissue localization of platinum as a function of NaCl concentration in the vehicle of administration., Toxicol Appl Pharmacol 61:99
Miller SE, House DA (1989) The hydrolysis products ofcis-diamminedichloroplatinum(II): 1. The kinetics of formation and anation of thecis-diammine(aqua)chloroplatinum(II) cation in acidic aqueous solution. Inorg Chim Acta 161:131
Miller SE, House DA (1990) The hydrolysis, products ofcis-diamminedichloroplatinum(II): 3. Hydrolysis kinetics at physiological pH. Inorg Chim Acta 173:53
Miller SK, Marzilli LG (1985) Interaction of platinum antitumor agents with guanosine nucleosides and nucleotides, [195Pt] and [1H]-NMR spectroscopic characterization of compound III. Inorg Chem 24:2421
Reznik LV, Myazina EM, Shakchmatova EI, Gambaryan SP, Brovtsyn VK, Natochin YV, Jones MM (1991) The prevention of cisplatin-induced renal dysfunction by hydroxyl-containing dithiocarbamates. Br J Cancer 63:234
Rosenberg B (1978) Platinum complex-DNA interactions and anticancer activity. Biochimie 60:859
Safirstein R, Winston J, Moel D, Dikman S, Guttenplan J (1987) Cisplatin nephrotoxicity; insights into mechanism. Int J Androl 10: 325
Sherman SE, Lippard SJ (1987) Structural aspects of platinum anticancer drug interactions with DNA. Chem Rev 87:1153
Smith E, Brock AP (1988) An in vitro study comparing the cytotoxicity of three platinum complexes with regard to the effect of thiol depletion. Br J Cancer 57:548
Uozumi J, Litterst CL (1985) The effect of cisplatin on renal ATPase activity in vivo and in vitro. Cancer Chemother Pharmacol 15:93
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jones, M.M., Basinger, M.A., Beaty, J.A. et al. The relative nephrotoxicity of cisplatin,cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat. Cancer Chemother. Pharmacol. 29, 29–32 (1991). https://doi.org/10.1007/BF00686332
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00686332