Journal
NEUROBIOLOGY OF DISEASE
Volume 18, Issue 2, Pages 305-313Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2004.09.013
Keywords
cisplatin; dorsal root ganglia; neuron; sensory neurotoxicity; apoptosis; platinum-DNA; PC 12 cells; rats; adducts; nerve growth factor
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Cisplatin causes apoptosis of dorsal root ganglia (DRG) neurons. The amount of platinum binding to DNA correlates with cisplatin toxicity in cancer cells(1). Cisplatin binds neuronal DNA more than a neuron-like dividing cell line (PC12); 10-fold at 24 h and 24-fold greater at 72 h. Difference in platinum accumulation was not due to dividing versus post-mitotic state, or to a difference in rate of repair. There was overall greater accumulation of platinum in DRG neurons. In vivo DNA-Platinum binding in adult (300 g) rat DRG was greater than in multiple other tissues. Concomitant treatment with high-dose NGF prevented cisplatin-mediated neuronal apoptosis in vitro but did not reduce adduct formation. Our results show that NGF does not alter platination of DNA, indicating that it interrupts the platinum death pathway after adduct formation. In addition, disproportionate platinum accumulation may explain why a drug aimed at killing rapidly dividing cells causes sensory neurotoxicity. (C) 2004 Elsevier Inc. All rights reserved.
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