title: 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.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Madison 53792.
authors.forename: R P
authors.initials: RP
authors.lastname: Rago
authors.forename: J M
authors.initials: JM
authors.lastname: Miles
authors.forename: R L
authors.initials: RL
authors.lastname: Sufit
authors.forename: D R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: G
authors.initials: G
authors.lastname: Wilding
mesh_terms: 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
chemical_list: D010710:Phosphates; D013498:Suramin; D003576:Electron Transport Complex IV