REVERSAL BY NGF OF CYTOSTATIC DRUG-INDUCED REDUCTION OF NEURITE OUTGROWTH IN RAT DORSAL-ROOT GANGLIA IN-VITRO

Cytostatic drugs, like cisplatin, vincristine and taxol, when given to cancer patients may cause peripheral neuropathies. We were interested in the potential neuroprotective effects of neurotrophic factors agai nst such neuropathies. To this aim we studied the effects of these cyt ostatic agents on sensory fibers located in the dorsal root ganglia (D RG) in vitro and studied whether nerve growth factor (NGF) could rever se the cytostatic induced morphological changes on intact DRG (1 DRG/w ell, n = 10 per dose). Neuritogenesis from DRG was measured with an im age analysis system following exposure to different concentrations of cytostatic drugs in the presence of 3 ng NGF/ml and cytosine arabinosi de (Ara-C, 10(-6) M). Relative neurite outgrowth in intact DRG in cult ure was reduced dose-dependently, (a) by vincristine starting at a dos e of 0.4 ng/ml for 2 days (-33% as compared to control; P < 0.001, Stu dent's t-test); (b) by taxol 10 ng/ml (-60%; P < 0.001), and (c) by ci splatin 3 mug/ml (-47%, P < 0.001). Cisplatin also prevented the migra tion of satellite cells away from the intact DRG along the extending n eurites into the well in contrast to control, vincristine, or taxol. T o evaluate the neuroprotective potential of NGF in this in vitro cytos tatic neuropathy model, we incubated intact DRG with cytostatic agents in combination with increasing amounts of NGF. Neurite outgrowth from DRG treated with vincristine (0.5 ng/ ml) + NGF (3 ng/ml) for 2 days was significantly higher (+87%) than after treatment with vincristine + 1 ng NGF/ ml (P < 0.001). Neurite outgrowth from DRG treated with ta xol (20 ng/ ml) + NGF (3 ng/ ml) for 2 days was significantly higher ( +228%) than after taxol + 1 ng NGF/ ml (P < 0.05). Neuritogenesis from DRG treated with cisplatin (2.5 mug/ml) + NGF (3 ng/ ml) for 2 days w as significantly increased (+105%) compared to treatment with cisplati n + 1 ng NGF/ ml (P < 0.001). DRG thus appear to be a very suitable mo del for studying cytostatic drug-induced neuropathies in vitro and NGF has a clear neuroprotective effect on the vincristine-, taxol-, and c isplatin-induced neuropathies in this in vitro model.