Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy.
The mechanism(s) and site(s) of the neurotoxic effect of cisplatin (CDDP) are still not entirely elucidated. A more detailed knowledge of these aspects of CDDP treatment might be useful to obtain a better understanding of the pathogenesis of its peripheral neurotoxicity, which is the dose-limiting side effect of CDDP. In the present study, the occurrence of CDDP-induced DNA-platination in dorsal root ganglia (DRG) of rats was evaluated in relation to DRG neuron pathological changes and CDDP-induced neuronopathy. Eight adult Wistar rats were treated with 2 mg/kg i.p. CDDP twice weekly for 9 times to induce sensory peripheral neuropathy. DNA-platination in specimens of DRG and kidney was measured immunohistochemically, with a polyclonal antibody (GPt) detecting CDDP-induced Pt-DNA adducts. Results were compared with those of untreated rats. Chronic CDDP-induced neurotoxicity, in a well described experimental model of chronic CDDP neurotoxicity in the Wistar rat, was confirmed by sensory DRG neuronopathy with secondary neuropathy, and demonstrated by reduced pain detection, decreased nerve conduction velocity in the tail nerve as well as morphological and morphometric changes in DRG neurons. Nuclear immunostaining for Pt-DNA adducts was observed in tubular cells of the kidney in 75% of the evaluated CDDP-treated rats, while in DRG cells CDDP-induced Pt-DNA adducts formation was found in 43% of the evaluated CDDP-treated rats. CDDP-induced DNA-platination was demonstrated in rat DRG neurons using a schedule of chronic CDDP administration which induced the onset of a sensory neuronopathy with secondary peripheral neuropathy. This finding further supports the hypothesis that CDDP is neurotoxic because it directly damages the DRG neurons.
Meijer
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C
Department of Medical Oncology, University Hospital Groningen, The Netherlands. j.meijer@int.azg.nl
de Vries
E G
EG
Marmiroli
P
P
Tredici
G
G
Frattola
L
L
Cavaletti
G
G
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D012678:Sensation Disorders / Q000139:chemically induced*; D013997:Time Factors
D000906:Antibodies; D000970:Antineoplastic Agents; D018736:DNA Adducts; D002945:Cisplatin