ETOPOSIDE-INDUCED AND BMY-40481-INDUCED SENSORY NEUROPATHY IN MICE

The effects of high toxic doses of the anticancer drugs, etoposide and its phosphate derivative, BMY-40481, on the nervous system of female CD-1 mice were examined by light microscopy (LM) and transmission elec tron microscopy. Mice were euthanatized 4 wk following a single iv inj ection of either 0, 50, 100, or 150 mg/kg of BMY-40481 or 44 or 88 mg/ kg of etoposide. Mice treated with 100 or 150 mg/kg of BMY-40481 or 88 mg/kg of etoposide had clinical symptomology of progressive ataxia, i mpaired righting reflex, and splaying and paresis of fore- and hindlim bs at day 8. Similar, dose-related LM changes were observed with both drugs at all doses and consisted of degeneration of dorsal root gangli on cells and axonal degeneration of their distal and proximal processe s in peripheral nerves, dorsal spinal roots, and dorsal funiculi of sp inal cord. Axonal degeneration was characterized by LM as shrinkage, s welling, and fragmentation of axon cylinders accompanied by secondary demyelination. Degenerative changes in ganglion cell bodies included e ccentric nuclei, cytoplasmic vacuolation, central chromatolysis, and p eripheral clumping of Nissl's bodies. Ultrastructurally, ganglion cell bodies had focally extensive dilation of the rough endoplasmic reticu lum, mitochondrial swelling, increased numbers of phagolysosomes and p rominent aggregations of microfilaments (globular filamentous bodies). Ultrastructural axonal changes occurred primarily in large, myelinate d fibers and consisted of axonal swelling or loss, thinning of myelin sheaths, and a decrease in the number of organelles. This is the first report of etoposide-related sensory neuropathy in laboratory animals, a model that may be useful for the study of etoposide-related periphe ral neuropathy in humans.