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The Journal of Neuroscience, August 29, 2007, 27(35):9451-9457; doi:10.1523/JNEUROSCI.0523-07.2007

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Cellular/Molecular
Repair Capacity for Platinum-DNA Adducts Determines the Severity of Cisplatin-Induced Peripheral Neuropathy

Anna Dzagnidze,¹ Zaza Katsarava,² Julia Makhalova,¹ Bernd Liedert,¹ Min-Suk Yoon,² Holger Kaube,^3,4 Volker Limmroth,² and Juergen Thomale¹

¹Institut für Zellbiologie (Tumorforschung) and ²Klinik für Neurologie, Universitätsklinikum der Universität Duisburg-Essen, D-45122 Essen, Germany, ³Department of Neurology and Neurophysiology, University of Freiburg, D-79095 Freiburg, Germany, and ⁴Division of Neurosciences, Medical School, Southampton University, Southampton SO16 64D, United Kingdom

Correspondence should be addressed to Dr. Juergen Thomale, Institute of Cell Biology, Cancer Research, University of Duisburg-Essen Medical School, Hufelandstrasse 55, D-45122 Essen, Germany. Email: Juergen.thomale{at}uni-essen.de

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.

Key words: DNA adducts; repair; cisplatin; polyneuropathy; monoclonal antibodies; dorsal root ganglion

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Received Feb. 6, 2007; revised June 26, 2007; accepted July 5, 2007.

Correspondence should be addressed to Dr. Juergen Thomale, Institute of Cell Biology, Cancer Research, University of Duisburg-Essen Medical School, Hufelandstrasse 55, D-45122 Essen, Germany. Email: Juergen.thomale{at}uni-essen.de

This article has been cited by other articles:

				S. R. McWhinney, R. M. Goldberg, and H. L. McLeod Platinum neurotoxicity pharmacogenetics Mol. Cancer Ther., January 1, 2009; 8(1): 10 - 16. [Abstract] [Full Text] [PDF]

				Y. Jiang, C. Guo, M. R. Vasko, and M. R. Kelley Implications of Apurinic/Apyrimidinic Endonuclease in Reactive Oxygen Signaling Response after Cisplatin Treatment of Dorsal Root Ganglion Neurons Cancer Res., August 1, 2008; 68(15): 6425 - 6434. [Abstract] [Full Text] [PDF]

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