title: Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity.
abstract: OBJECTIVE
  To identify the major sites of platinum accumulation within neural tissues after treatment with cisplatin and to determine the relationship between cumulative dosage, time, and the development of histopathological and clinical neurotoxicity.
  
  
  METHODS
  Twenty-one patients treated antemortem with cisplatin had neural tissue harvested at autopsy. Neural tissues were assayed for platinum and examined for histopathologic evidence of neurotoxicity. The relationship between histopathologic neurotoxicity and various pharmacologic parameters was analyzed.
  
  
  RESULTS
  Tissue platinum levels were found to be highest in the dorsal root ganglia and lowest in tissue protected by the blood-brain barrier. For peripheral nerve, dorsal root, and dorsal root ganglia, a linear relationship was observed between platinum levels and cumulative dose. Platinum levels in neural tissue were not observed to decrease with time. Histopathologic toxicity closely matched an index of exposure to platinum (cumulative dose and log of time). Clinical and histopathologic neurotoxicity was found to occur with higher accumulations of platinum, with the highest levels found in patients with clinical evidence of neurotoxicity.
  
  
  CONCLUSIONS
  The dorsal root ganglia was the most vulnerable neural structure. This is consistent with the clinical presentation of sensory neuropathy in cisplatin neurotoxicity. Central structures of the spinal cord and brain were protected from platinum accumulation. The increasing histopathologic toxicity, with an index of exposure to platinum, suggests that it is retained indefinitely in an actively neurotoxic form. The pharmacologic parameters examined correlate with the development of and are consistent with the clinical and laboratory features of cisplatin neurotoxicity.
authors.affiliation: Ontario Cancer Treatment and Research Foundation, Ottawa Regional Cancer Center, Canada.
authors.forename: R W
authors.initials: RW
authors.lastname: Gregg
authors.forename: J M
authors.initials: JM
authors.lastname: Molepo
authors.forename: V J
authors.initials: VJ
authors.lastname: Monpetit
authors.forename: N Z
authors.initials: NZ
authors.lastname: Mikael
authors.forename: D
authors.initials: D
authors.lastname: Redmond
authors.forename: M
authors.initials: M
authors.lastname: Gadia
authors.forename: D J
authors.initials: DJ
authors.lastname: Stewart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
chemical_list: D002945:Cisplatin