THE EFFECT OF NERVE GROWTH-FACTOR, CILIARY NEUROTROPHIC FACTOR, AND ACTH ANALOGS ON CISPLATIN NEUROTOXICITY IN-VITRO

Cisplatin, used to treat ovarian, bladder, and testicular cancers, causes a sensory dose-limiting neuropathy. Preliminary observations in humans and animals suggest that nerve damage may be prevented by ACTH analogs, particularly those belonging to the melanocortin class, and by nerve growth factor (NGF). We established a rat embryo dorsal root ganglion model to study cisplatin neurotoxicity. The drug reproducibly inhibited axonal growth at concentrations similar to that known to produce toxicity in neurons. The inhibition was prevented in a dose-dependent fashion by simultaneous exposure to alpha-melanocyte stimulating hormone (alpha-MSH) or ACTH4-9) but not by excess NGF or ciliary neurotrophic factor (CNTF). The ACTH peptides were not effective in preventing suramin-induced neurotoxicity in the same model. Drug interaction and dose-response studies showed that ACTH4-9 and alpha-MSH do not act by potentiation of NGF action. ACTH analogs appear to protect against cisplatin-induced neurotoxicity directly at the cellular level.