Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding.
Cisplatin has been in use for 40 years, primarily for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Neurotoxicity occurs in up to 30% of patients and is dose-limiting for both drugs. The neuropathy is characterized by selective sensory loss in the extremities. Cisplatin treatment is associated with high levels of Pt-DNA binding and apoptosis of dorsal root ganglion (DRG) neurons. In this study, we directly compared the effects of oxaliplatin on DRG in vitro. Compared with cisplatin, oxaliplatin formed fewer Pt-DNA adducts following 6, 12, 24, and 48h (0.007ng Pt/mug DNA, 0.012ng/microg, 0.011ng/microg, 0.011ng/microg versus 0.014ng/microg, 0.022ng/microg, 0.041ng/microg, 0.030ng/microg), respectively. These findings closely correlated with data on cell survival where equimolar concentrations of oxaliplatin induced less cell death than cisplatin. Oxaliplatin-induced DRG death was associated with the morphological characteristics of apoptosis defined by 4'-6-diamidino-2-phenylindole and annexin/propidium iodide staining. Death was completely inhibited by the caspase inhibitor z-VAD-fmk. Our results demonstrate that both compounds cause apoptosis of DRG neurons but compared to cisplatin, oxaliplatin forms fewer Pt-DNA adducts and is less neurotoxic to DRG neurons in vitro.
Ta
Lauren E
LE
Molecular Neuroscience Program and Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Espeset
Laura
L
Podratz
Jewel
J
Windebank
Anthony J
AJ
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017302:Annexins / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010984:Platinum / Q000493:pharmacokinetics*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D000590:Amino Acid Chloromethyl Ketones; D017302:Annexins; D018736:DNA Adducts; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009944:Organoplatinum Compounds; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000077150:Oxaliplatin; D010984:Platinum; D004247:DNA; D002945:Cisplatin