TY - JOUR
T1 - Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding
AU - Ta, Lauren E.
AU - Espeset, Laura
AU - Podratz, Jewel
AU - Windebank, Anthony J.
N1 - Funding Information:
The authors would like to acknowledge the great support of Steve Eckdahl and the Mayo Metals Laboratory and Jim Tarara and the Mayo Flow Cytometry/Optical Morphology Research Core Facility. This work was supported by National Institute of Neurological Disorders R01 NS 40471-04 (AJW) and National Institute of Dental and Craniofacial Research K08 DE14571-03 (LET).
PY - 2006/12
Y1 - 2006/12
N2 - 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 48 h (0.007 ng Pt/μg DNA, 0.012 ng/μg, 0.011 ng/μg, 0.011 ng/μg versus 0.014 ng/μg, 0.022 ng/μg, 0.041 ng/μg, 0.030 ng/μg), 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.
AB - 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 48 h (0.007 ng Pt/μg DNA, 0.012 ng/μg, 0.011 ng/μg, 0.011 ng/μg versus 0.014 ng/μg, 0.022 ng/μg, 0.041 ng/μg, 0.030 ng/μg), 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.
KW - Apoptosis
KW - Cell survival
KW - Platinum-nuclear binding
KW - z-VAD-fmk
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U2 - 10.1016/j.neuro.2006.04.010
DO - 10.1016/j.neuro.2006.04.010
M3 - Article
C2 - 16797073
AN - SCOPUS:33751534848
SN - 0161-813X
VL - 27
SP - 992
EP - 1002
JO - NeuroToxicology
JF - NeuroToxicology
IS - 6
ER -