Protection by an ACTH4-9 analogue against the toxic effects of cisplatin and taxol on sensory neurons and glial cells in vitro.
Sensory neuropathy is a serious side effect of anti-tumour drugs such as cisplatin and taxol. There are indications that an analogue of the adrenocorticotrophic hormone 4-9 fragment (ACTH4-9: Met(O2)-Glu-His-Phe-D-Lys-Phe) can prevent these neurotoxic effects. We studied the potential protective effects of this analogue in cultures of chick dorsal root ganglia and rat Schwann cells treated with cisplatin or taxol to gain insight into the mode of action and characteristics of this neuroprotection. Neurite outgrowth of sensory neurons in vitro was dose-dependently inhibited by cisplatin and taxol; after 48 hr, 10 micrograms/ml cisplatin reduced outgrowth from 431 +/- 17 microns to 220 +/- 6 microns and 0.01 micrograms/ml taxol from 344 +/- 3 microns to 200 +/- 43 microns. Co-treatment of 10 micrograms/ml cisplatin with the ACTH4-9 analogue (0.1 nM-1 nM) resulted in about 35% more outgrowth than cisplatin alone. In contrast, the analogue could not prevent taxol neurotoxicity. Migration of neurons and satellite cells from the DRG-body is completely inhibited by 10 micrograms/ml cisplatin. Taxol had no effect on the migration of these cells. In addition, cisplatin was more toxic to Schwann cells than taxol; 3-10 micrograms/ml cisplatin significantly reduced their laminin content, total protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase activity, and cell division. The ACTH4-9 analogue (0.01 nM-100 nM) had no effect on the migration of cells out of the DRGs and could not prevent the toxic effect on the Schwann cells. These data support our hypothesis that the neuroprotective effect of ACTH4-9 analogue is brought about by a direct action on neurons, possibly by replacing a Schwann-/satellite-cell derived trophic factor.
Department of Neurology, Utrecht University, The Netherlands.
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D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D007797:Laminin / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects*; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000633:toxicity; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects*; D012584:Sciatic Nerve / Q000166:cytology; D012678:Sensation Disorders / Q000139:chemically induced / Q000517:prevention & control
D007797:Laminin; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C028024:ACTH (4-9); D000324:Adrenocorticotropic Hormone; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D017239:Paclitaxel; D002945:Cisplatin