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.
Pradat
P F
PF
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.
Finiels
F
F
Kennel
P
P
Naimi
S
S
Orsini
C
C
Delaere
P
P
Revah
F
F
Mallet
J
J
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