Nucleolar damage correlates with neurotoxicity induced by different platinum drugs

Platinum-based drugs are very useful in cancer therapy but are associated w ith neurotoxicity in the clinic. To investigate the mechanism of neurotoxic ity, dorsal root ganglia of rats treated with various platinum drugs were s tudied. Cell body, nuclear and nucleolar dimensions of dorsal root ganglia sensory nerve cells were measured to determine morphological toxicity. Sens ory 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 m aximal at 24 hours, recovered very slowly and showed a non-linear dependenc e on oxaliplatin dose (r(2) = 0.99). Functional toxicity was delayed in ons et until 14 days after a single dose of oxaliplatin but eventually recovere d 3 months after treatment. Multiple doses of cisplatin, carboplatin, oxali platin, R, R-ormaplatin and S, S-ormaplatin were also associated with time- dependent reduction in nucleolar size. A linear correlation was obtained be tween the rate of change in nucleolar size during multiple dose treatment w ith the series of platinum drugs and the time taken for the development of altered sensory nerve conduction velocity (r(2) = 0.86; P < 0.024). Damage to the nucleolus of ganglionic sensory neurons is therefore linked to the n eurotoxicity of platinum-based drugs, possibly through mechanisms resulting in the inhibition of rRNA synthesis. (C) 2001 Cancer Research Campaign.