Regular Article

British Journal of Cancer (2001) 85, 1219–1225. doi:10.1054/bjoc.2001.2024 www.bjcancer.com
Published online 16 October 2001

Nucleolar damage correlates with neurotoxicity induced by different platinum drugs

M J McKeage1, T Hsu1, D Screnci1, G Haddad1 and B C Baguley2

  1. 1Division of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, The University of Auckland, Auckland, New Zealand
  2. 2Auckland Cancer Society Research Centre, Faculty of Medicine and Health Sciences, The University of Auckland, Auckland, New Zealand

Received 28 March 2001; Revised 19 June 2001; Accepted 21 June 2001.

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Abstract

Platinum-based drugs are very useful in cancer therapy but are associated with neurotoxicity in the clinic. To investigate the mechanism of neurotoxicity, dorsal root ganglia of rats treated with various platinum drugs were studied. Cell body, nuclear and nucleolar dimensions of dorsal root ganglia sensory nerve cells were measured to determine morphological toxicity. Sensory nerve conduction velocity was measured to determine functional toxicity. After a single dose of oxaliplatin (10 mg kg–1), no significant change in nuclear and cell body diameter was seen but decreased nucleolar size was apparent within a few hours of treatment. Changes in nucleolar size were maximal at 24 hours, recovered very slowly and showed a non-linear dependence on oxaliplatin dose (r2= 0.99). Functional toxicity was delayed in onset until 14 days after a single dose of oxaliplatin but eventually recovered 3 months after treatment. Multiple doses of cisplatin, carboplatin, oxaliplatin, R, R -ormaplatin and S, S -ormaplatin were also associated with time-dependent reduction in nucleolar size. A linear correlation was obtained between the rate of change in nucleolar size during multiple dose treatment with the series of platinum drugs and the time taken for the development of altered sensory nerve conduction velocity (r2= 0.86;P< 0.024). Damage to the nucleolus of ganglionic sensory neurons is therefore linked to the neurotoxicity of platinum-based drugs, possibly through mechanisms resulting in the inhibition of rRNA synthesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

platinum drugs, cancer chemotherapy, neurotoxicity, dorsal root ganglia, nucleolus

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