Suramin-induced weakness from hypophosphatemia and mitochondrial myopathy. Association of suramin with mitochondrial toxicity in humans

Abstract

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.