Partial prevention of cisplatin-induced neuropathy by electroporation-mediated nonviral gene transfer.
Cisplatin-induced sensory peripheral neuropathy is the dose-limiting factor for cisplatin chemotherapy. We describe the preventive effect of NT-3 delivery, using direct gene transfer into muscle by in vivo electroporation in a mouse model of cisplatin-induced neuropathy. Cisplatin-induced neuropathy was produced by weekly injections of cisplatin (five injections). Two doses of plasmid DNA encoding murine NT-3 (pCMVNT-3) were tested (5 and 50 microg/animal/injection). Cisplatin-treated mice were given two intramuscular injections. The first injection of pCMVNT-3 was given 2 days before the first injection of cisplatin and the second injection 2 weeks later. Six weeks after the start of the experiment, measurement of NT-3 levels (ELISA) demonstrated significant levels both in muscle and plasma. We observed a smaller cisplatin-related increase in the latency of the sensory nerve action potential of the caudal nerve in pCMVNT-3-treated mice than in controls (p < 0.0001). Mean sensory distal latencies were not different between the 5- and 50- microg/animal/injection groups. Treatment with gene therapy induced only a slight muscle toxicity and no general side effects. Therefore, neurotrophic factor delivery by direct gene transfer into muscle by electroporation is of potential benefit in the prevention of cisplatin-induced neuropathy and of peripheral neuropathies in general.
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR C9923, Centre National de la Recherche Scientifique, Hôpital de la Pitié-Salpétriere, 75651 Paris Cedex 13, France.
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Pradat
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Finiels
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Kennel
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Naimi
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Orsini
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Delaere
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Revah
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Mallet
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000009:adverse effects*; D018274:Electroporation / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D018014:Gene Transfer Techniques; D007124:Immunoenzyme Techniques; D007273:Injections, Intramuscular; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D009475:Neurons, Afferent / Q000473:pathology*; D020933:Neurotrophin 3 / Q000235:genetics* / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010957:Plasmids
D000970:Antineoplastic Agents; D020933:Neurotrophin 3; D002945:Cisplatin