Enzymuria in Cisplatin-Induced Kidney Damage as an Index of its Reversal by Combined Treatment with Diethyldithiocarbamate

Abstract

The nephrotoxicity of cis-dichlorodiammine platinum (II) (DDP) is the most serious dose-limiting factor for its therapeutic use. The important finding by Borch and Pleasants (1) that sodium diethyl-dithiocarbamate (DDTC) could partially inhibit DDP nephrotoxicity without adverse effects on tumor response has been confirmed by us (2,3) and by several other investigators (4,5). Since the nephrotoxicity of DDP is related to the damage of proximal tubule, our interest was focused on the earliest signes of this damage. Enzyme excretion has been proposed to be a sensitive noninvasive, nondestructive test of renal toxicity (6–8). Urine enzymes studies have chiefly focused on enzymes of lysosomal or intracellular origin. These enzymes are widely distributed and, because of their intracellular localization, their urinary excretion might be expected to increased only with cell death and lysis. Therefore we chose N-acetil-β-glucaminidase (NAG), a lysosomal enzyme (9) and α-glucosidase (α-GLUC), an enzyme contained only in the lysosomes of proximal renal tubular cells (10), as markers of DDP and DDTC toxicity after single administration and three combined treatments in which DDTC was administered 1 hr before or 1 and 5 hrs after DDP, respectively.