Renal toxicity of the anticancer drug fostriecin.
OBJECTIVE
Fostriecin is an inhibitor of topoisomerase II catalytic activity. In a phase I trial we observed renal toxicity, documented as a rise in serum creatinine, which was reversible and non-dose-limiting. The purpose of this study was a detailed analysis of this toxicity.


METHODS
A total of 20 patients received fostriecin as a 1-h i.v. infusion daily x 5 at doses ranging from 2 to 20 mg/m2 per day. Serum creatinine determination and urinalysis were performed daily during drug administration. Renal hemodynamics were measured by means of clearance studies using 125I-iothalamate and (131)I-hippuran in eight patients at doses of > or =4 mg/m2 per day at baseline, on day 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 doses despite continued administration. This increase showed no correlation with the dose level at fostriecin doses of > or =4 mg/m2 per day. Urinary beta2-microglobulin concentrations increased 150-fold (median), which is compatible with impaired tubular reabsorption. The median change in the glomerular filtration rate (GFR) was -36% (range -28% to -44%), that in effective renal plasma flow (ERPF) was -23% (range -11% to -36%), and the filtration fraction (FF) decreased in all patients during the first course of treatment. The values measured 3 weeks after the second course, however, did not differ from baseline.


CONCLUSIONS
Fostriecin induces reversible renal hemodynamic changes compatible with renal tubular damage.
de Jong
R S
RS
Department of Internal Medicine, Groningen University Hospital, The Netherlands.
de Vries
E G
EG
Meijer
S
S
de Jong
P E
PE
Mulder
N H
NH
D000328:Adult; D000368:Aged; D000475:Alkenes / Q000009:adverse effects / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D003401:Creatine / Q000097:blood; D004573:Electrolytes / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D011090:Polyenes; D011753:Pyrones; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D014508:Urea / Q000097:blood
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D004573:Electrolytes; D011090:Polyenes; D011753:Pyrones; D014508:Urea; D003401:Creatine; C040313:fostriecin