Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity.
Cisplatin causes apoptosis of dorsal root ganglia (DRG) neurons. The amount of platinum binding to DNA correlates with cisplatin toxicity in cancer cellsGenomic DNA platinum content of cultured embryonic DRG neurons and PC12 cells was assayed using inductively coupled plasma mass spectrometry (ICP-MS). Throughout these studies, "cisplatin" refers to the specific drug; "platinum" to the bound form of the drug that is measured in ICP-MS.. 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.
McDonald
Elizabeth S
ES
Molecular Neuroscience Program, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Randon
Kelli R
KR
Knight
Andrew
A
Windebank
Anthony J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D020932:Nerve Growth Factor / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D016716:PC12 Cells; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D010984:Platinum / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009498:Neurotoxins; D010984:Platinum; D004247:DNA; D020932:Nerve Growth Factor; D002945:Cisplatin