RENAL TOXICITY OF THE ANTICANCER DRUG FOSTRIECIN

Purpose: Fostriecin is an inhibitor of topoisomerase II catalytic acti vity. In a phase I trial we observed renal toxicity, documented as a r ise in serum creatinine, which was reversible and non-dose-limiting. T he purpose of this study was a detailed analysis of this toxicity. Met hods: A total of 20 patients received fostriecin as a 1-h i.v. infusio n daily x 5 at doses ranging from 2 to 20 mg/m(2) per day. Serum creat inine determination and urinalysis were performed daily during drug ad ministration. Renal hemodynamics were measured by means of clearance s tudies using I-125-iothalamate and I-131-hippuran in eight patients at doses of greater than or equal to 4 mg/m(2) per day at baseline, on d ay 3 or 4 during the first course, and 3 weeks after the second course . Results: The rise in serum creatinine was maximal after one to two d oses despite continued administration. This increase showed no correla tion with the dose level at fostriecin doses of greater than or equal to 4 mg/m(2) per day. Urinary beta(2)-microglobulin concentrations inc reased 150-fold (median), which is compatible with impaired tubular re absorption. The median change in the glomerular filtration rate (GFR) was -36% (range -28% to -44%), that in effective renal plasma flow (ER PF) was -23% (range -11% to -36%), and the filtration fraction (FF) de creased in all patients during the first course of treatment. The valu es measured 3 weeks after the second course, however, did not differ f rom baseline. Conclusions: Fostriecin induces reversible renal hemodyn amic changes compatible with renal tubular damage.