The evolution of cellular degeneration in dorsal root ganglia exposed to doxorubicin in tissue culture

Doxorubicin (Adriamycin®) is a drug having both antibiotic and antimitotic properties. It intercalates between base pairs of DNA causing breaks in the helical strands. It is widely used as a cancer chemotherapeutic agent but is limited in use by a dose-related cardiomyopathy and necrosis of peripheral ganglia. This study of cultured mouse spinal cord and dorsal root ganglia examined the sequential pathological changes of living tissue by light and fluoresence microscopy and of fixed tissue by electron microscopy. Fluorescence microscopy showed that doxorubicin has rapid access to ganglia cells and preferentially binds to the nucleus and nucleolus. Pathological changes of the peripheral neurons include clumping of nuclear chromatin, relocation of the indented nucleus to an eccentric position, occasional loss of the nuclear envelope, dissociation of the nucleolus into the pars granulosa and the pars fibrosa, accumulation of inclusion bodies in the cytoplasm, swollen cistemae and a loss of Nissl substance. Axons display changes in localization of organelles prior to undergoing proximal Wallerian-like degeneration. Schwann cells occasionally display clumped nuclear chromatin. Some satellite cells undergo necrosis. These findings are dose- and time-related and essentially duplicate those previously reported in animal studies. Thus, the in vitro model may provide a useful tool for ascertaining the sequence of events occurring in sensory neuronopathy.