Suramin-induced weakness from hypophosphatemia and mitochondrial myopathy. Association of suramin with mitochondrial toxicity in humans.
BACKGROUND
Suramin is an antiparasitic drug being evaluated as an antitumor compound. Suramin therapy commonly causes weakness and is known to cause neuropathy. Two potential causes of suramin-induced muscular weakness are described.


METHODS
Suramin was administered to 15 patients with advanced cancer as part of a Phase I study. Weekly dosing was adjusted to achieve mean plasma concentrations of 210 micrograms/ml.


RESULTS
Serum phosphate levels fell significantly (P < 0.0001) in all 15 patients on the 42nd day of treatment from a pretreatment average of 4.0 mg/dl (standard deviation [SD] +/- 0.37) to 3.0 mg/dl (SD +/- 0.20). Absolute hypophosphatemia developed in two patients with more prolonged suramin treatment due to Fanconi's syndrome. The patient who received the largest amount of suramin (19.2 g over 14 weeks) had severe proximal muscle weakness despite 6 weeks of effective phosphate repletion. A muscle biopsy was performed, which demonstrated markedly decreased cytochrome c oxidase activity by muscle histochemistry and biochemistry. Electron microscopy revealed subsarcolemmal collections of abnormal mitochondria. This mitochondrial myopathy resolved clinically 7 weeks after discontinuing suramin.


CONCLUSIONS
This report indicates that suramin is associated with hypophosphatemia of Fanconi's syndrome and a mitochondrial myopathy. The clinical combination of mitochondrial myopathy and Fanconi's syndrome is similar to descriptions of congenital mitochondrial cytochrome c oxidase deficiency of de Toni-Fanconi-Debré syndrome. These findings in humans correlate with the authors' in vitro observations that suramin causes toxic mitochondrial changes, indicating a mechanism of suramin's toxicity and possibly its antitumor effect.
Rago
R P
RP
University of Wisconsin Comprehensive Cancer Center, Madison 53792.
Miles
J M
JM
Sufit
R L
RL
Spriggs
D R
DR
Wilding
G
G
D003576:Electron Transport Complex IV / Q000032:analysis; D005198:Fanconi Syndrome / Q000097:blood / Q000139:chemically induced*; D006801:Humans; D017674:Hypophosphatemia / Q000097:blood / Q000139:chemically induced*; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D009123:Muscle Hypotonia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D009132:Muscles / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D010710:Phosphates / Q000097:blood / Q000652:urine; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013498:Suramin / Q000009:adverse effects* / Q000097:blood; D013997:Time Factors
D010710:Phosphates; D013498:Suramin; D003576:Electron Transport Complex IV