INSULIN-LIKE GROWTH-FACTOR-I PREVENTS DEVELOPMENT OF A VINCRISTINE NEUROPATHY IN MICE

Vincristine is a commonly used antitumor agent whose major dose-limiti ng side-effect is a mixed sensorimotor neuropathy. To assess whether i nsulin-like growth factor-I (IGF-I), a neurotrophic agent that support s the survival of motoneurons and enhances regeneration of motor and s ensory neurons, could prevent the peripheral neuropathy produced by vi ncristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 X/week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mic e treated with vincristine alone, there was evidence of a mixed sensor imotor neuropathy as indicated by changes in behavior, nerve conductio n and histology. Caudal nerve conduction velocity was significantly sl ower in mice treated with vincristine alone as compared with vehicle-t reated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but no t toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristi ne-treated mice prevented the neurotoxic effects of vincristine as mea sured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I part ially ameliorated the neuropathy induced by vincristine as this dose o nly prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. The se results suggest that IGF-I prevents both motor and sensory componen ts of vincristine neuropathy and may be useful clinically in preventin g the neuropathy induced by vincristine treatment. (C) 1997 Elsevier S cience B.V.