Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: A potential mechanism for neurotoxicity

Elizabeth S. McDonald, Kelli R. Randon, Andrew Knight, Anthony J. Windebank

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Cisplatin causes apoptosis of dorsal root ganglia (DRG) neurons. The amount of platinum binding to DNA correlates with cisplatin toxicity in cancer cells1. Cisplatin binds neuronal DNA more than a neuron-like dividing cell line (PC12); 10-fold at 24 h and 24-fold greater at 72 h. Difference in platinum accumulation was not due to dividing versus post-mitotic state, or to a difference in rate of repair. There was overall greater accumulation of platinum in DRG neurons. In vivo DNA-Platinum binding in adult (300 g) rat DRG was greater than in multiple other tissues. Concomitant treatment with high-dose NGF prevented cisplatin-mediated neuronal apoptosis in vitro but did not reduce adduct formation. Our results show that NGF does not alter platination of DNA, indicating that it interrupts the platinum death pathway after adduct formation. In addition, disproportionate platinum accumulation may explain why a drug aimed at killing rapidly dividing cells causes sensory neurotoxicity.

Original languageEnglish (US)
Pages (from-to)305-313
Number of pages9
JournalNeurobiology of Disease
Volume18
Issue number2
DOIs
StatePublished - Mar 2005

Keywords

  • Adducts
  • Apoptosis
  • Cisplatin
  • Dorsal root ganglia
  • Nerve growth factor
  • Neuron
  • PC12 cells
  • Platinum-DNA
  • Rats
  • Sensory neurotoxicity

ASJC Scopus subject areas

  • Neurology

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