The effect of nerve growth factor, ciliary neurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro

Abstract

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 ACTH 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 ACTH 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.

Neurotrophic Factors and Diabetic Peripheral Neuropathy

“…In tissue culture, Konings et al [31]have reported that NGF could prevent cisplatin-induced inhibition of neurite outgrowth in vitro. Windebank et al [38], however, demonstrated that NGF was unable to prevent cisplatin-induced inhibition of neurite outgrowth in dorsal root ganglion explant cultures [38]. In a mouse model of cisplatin-induced neuropathy, we demonstrated that NGF could prevent behavioural, biochemical and electrophysiological manifestations of large-fibre dysfunction [39].…”

Vitamin E neuroprotection for cisplatin neuropathy

“…Neuroprotection by antioxidants has therefore drawn much interest. 11,23 Antioxidants may protect against systemic toxicity and neurotoxicity by bonding to free radicals and preventing oxidative damage. Most of the available research on the role of antioxidant nutrients in neurologic function and disease has focused on vitamin E. Vitamin E is the most common lipid-soluble, chain-breaking antioxidant in Table 1 Distribution of patients Table 2 Clinical and neurophysiologic data (mean ؎ SD) assessed before treatment (basal) and after 6 cycles of cisplatin the body, protecting the integrity of membranes by inhibiting lipid peroxidation.…”

Lack of neuroprotection by an ACTH (4?9) analogue. A randomized trial in patients treated with vincristine for Hodgkin?s or non-Hodgkin?s lymphoma

“…No significant differences were observed between the placebo and actively treated group for the major and secondary endpoints. Conclusion: Contrary to a single previous pilot study in patients receiving VCR-based chemotherapy, in our study the ACTH (4-9) analogue Org 2766 did not provide protection from VCR-induced neuropathy.Keywords Neuroprotection AE ACTH (4-9) analogue AE Vincristine-induced neuropathy clinical setting (Mu¨ller et al 1992;Gispen 1993;De Koning et al 1987b;Gerritsen van der Hoop et al 1994;Gerritsen van der Hoop et al 1988;Windebank et al 1994;Russell et al 1995). It had no stimulatory effects on human lymphoma cell lines and did not negatively…”