PROTECTION BY AN ACTH(4-9) ANALOG AGAINST THE TOXIC EFFECTS OF CISPLATIN AND TAXOL ON SENSORY NEURONS AND GLIAL-CELLS IN-VITRO

Sensory neuropathy is a serious side effect of antitumour drugs such a s cisplatin and taxol. There are indications that an analogue of the a drenocorticotrophic hormone 4-9 fragment (ACTH(4-9): Met(O-2)-Glu-His- Phe-D-Lys-Phe) can prevent these neurotoxic effects. We studied the po tential protective effects of this analogue in cultures of chick dorsa l root ganglia and rat Schwann cells treated with cisplatin or taxol t o gain insight into the mode of action and characteristics of this neu roprotection. Neurite outgrowth of sensory neurons in vitro was dose-d ependently inhibited by cisplatin and taxol; after 48 hr, 10 mu g/ml c isplatin reduced outgrowth from 431 +/- 17 mu m to 220 +/- 6 mu m and 0.01 mu g/ml taxol from 344 +/- 3 mu m to 200 +/- 43 mu m. Co-treatmen t of 10 mu g/ml cisplatin with the ACTH(4-9) analogue (0.1 nM-1 nM) re sulted in about 35% more outgrowth than cisplatin alone. In contrast, the analogue could not prevent taxol neurotoxicity. Migration of neuro ns and satellite cells from the DRG-body is completely inhibited by 10 mu g/ml cisplatin. Taxol had no effect on the migration of these cell s. In addition, cisplatin was more toxic to Schwann cells than taxol; 3-10 mu g/ml cisplatin significantly reduced their laminin content, to tal protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase activity, an d cell division. The ACTH(4-9) analogue (0.01 nM-100 nM) had no effect on the migration of cells out of the DRGs and could not prevent the t oxic effect on the Schwann cells. These data support our hypothesis th at the neuroprotective effect of ACTH(4-9) analogue is brought about b y a direct action on neurons, possibly by replacing a Schwann-/satelli te-cell derived trophic factor. (C) 1994 Wiley-Liss, Inc.