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.