Selected Aspects of Cisplatin Nephrotoxicity in the Rat and Man

Abstract

Gastrointestinal toxi city, nephrotoxicity, peripheral neuropathy, and progressive anemia are each side effects of high-dose intermittent cisplatin therapy. We have characterized each of these toxicities in a Clinical Research Center setting in about 100 patients, who received 5 to 10 monthly courses of therapy. We have attempted to define the molecular bases for some of them and have begun to use the information generated to design and test methods of lessening these toxicities. Studies in rats first defined the circadian stage dependence of cisplatin pharmacology and nephrotoxicity. Clinical studies have since documented much higher urinary cisplatin concentrations when the drug is given in the morning as compared to the evening. Cisplatin nephrotoxicity can be largely avoided by administering the drug at the time of day associated with highest daily potassium excretion for that individual (usually in the late afternoon). A multivariate analysis of kidney toxicity data further revealed that older patients tolerated cisplatin therapy as well as, or better than, their younger counterparts. Additionally, cisplatin nephrotoxicity was only one-third as great in a subset of 14 patients with a single kidney. The amount of gastrointestinal toxicity also depends to some extent upon what time of day the drug is given. The neurotoxicity of cisplatin was defined and quantitated by serial graded clinical examinations, EMG and nerve conduction studies, and light and EMG studies of sural nerve biopsies. This toxicity is an irreversible predominantly sensory peripheral neuropathy. Although cisplatin binds avidly to B12 in vitro, we find no evidence for blockage of the B12-dependent conversion of malonic acid to malonyl COA or homocysteine to methionine (each necessary for the production of fatty acids and myelin). B12 therapy does not seem to prevent this toxicity. Cisplatin-induced anemia is normochromic and normocytic. Serum B12, B12 binding capacity, serum and red cell folates are normal. There was absolutely no evidence for hemolysis. Reticulocyte counts were low, and the bone marrow examination revealed that red cell precursors were generally decreased. Serum iron concentration, total iron binding capacity, transferrin, and ferritin were each quite high. Liver and bone marrow showed increased iron stores. Erythropoietin values were much lower than they would be expected to be, given the degree of anemia observed. These data point to an interference with iron utilization. Cisplatin effects upon heme and globin synthesis and ferrochetolase activity were also studied. Disulfiram therapy in mice bearing L1210 leukemia decreases cisplatin lethal toxicity and increases antitumor effect. The effect of disulfiram rescue upon cisplatin pharmacokinetics and toxicity was also studied in patients with encouraging results. Selective chemical and temporal modification of various cisplatin toxicities may serve as a model for the manipulation of therapeutic indices of other toxic yet active drugs.