Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy.
The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine-guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.
Dzagnidze
Anna
A
Institut für Zellbiologie (Tumorforschung), Universitätsklinikum der Universität Duisburg-Essen, D-45122 Essen, Germany.
Katsarava
Zaza
Z
Makhalova
Julia
J
Liedert
Bernd
B
Yoon
Min-Suk
MS
Kaube
Holger
H
Limmroth
Volker
V
Thomale
Juergen
J
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002945:Cisplatin; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009431:Neural Conduction / Q000502:physiology / Q000528:radiation effects; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009944:Organoplatinum Compounds / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D010984:Platinum / Q000493:pharmacokinetics*; D013997:Time Factors; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics
D018736:DNA Adducts; D003848:Deoxyguanine Nucleotides; D009944:Organoplatinum Compounds; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D010984:Platinum; C045231:diammine(2'-deoxyguanylyl-(5'-3')-2'-deoxy-5'-guanylyl)platinate; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D002945:Cisplatin