Premium
Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan
Author(s) -
Blandizzi Corrado,
De Paolis Barbara,
Colucci Rocchina,
Lazzeri Gloria,
Baschiera Fabio,
Del Tacca Mario
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703766
Subject(s) - physostigmine , irinotecan , acetylcholine , cholinergic , pharmacology , chemistry , acetylcholinesterase , endocrinology , medicine , atropine , biochemistry , colorectal cancer , cancer , enzyme
This study investigates the mechanisms accounting for the adverse cholinergic effects of the antitumour drug irinotecan. The activity of irinotecan and its active metabolite, 7‐ethyl‐10‐hydroxy‐camptothecin (SN‐38), was assayed in models suitable for pharmacological studies on cholinergic system. Irinotecan moderately inhibited human or electric eel acetylcholinesterase activity, SN‐38 had no effect, whereas physostigmine blocked both the enzymes with high potency and efficacy. Irinotecan and SN‐38 did not affect spontaneous or electrically‐induced contractile activity of human colonic muscle. Acetylcholine and dimethylphenylpiperazinium (DMPP) caused phasic contractions or relaxations, respectively. Physostigmine enhanced the motor responses elicited by electrical stimulation. Although irinotecan and SN‐38 did not modify the basal contractile activity of guinea‐pig ileum longitudinal muscle strips, irinotecan 100 μ M moderately enhanced cholinergic twitch contractions. Acetylcholine or DMPP caused phasic contractions, whereas physostigmine enhanced the twitch responses. Electrically‐induced [ 3 H]‐acetylcholine release was reduced by irinotecan (100 μ M ) or physostigmine (0.1 μ M ). Intravenous irinotecan stimulated gastric acid secretion in rats, but no effects were obtained with SN‐38, physostigmine or i.c.v. irinotecan. Hypersecretion induced by irinotecan was partly prevented by ondansetron, and unaffected by capsazepine. In the presence of atropine, vagotomy and systemic or vagal ablation of capsaicin‐sensitive afferent fibres, irinotecan did not stimulate gastric secretion. The present results indicate that irinotecan and SN‐38 do not act as specific acetylcholinesterase blockers or acetylcholine receptor agonists. It is rather suggested that irinotecan promotes a parasympathetic discharge to peripheral organs, mediated by capsaicin‐sensitive vagal afferent fibres, and that serotonin 5‐HT 3 receptors are implicated in the genesis of vago‐vagal reflex triggered by irinotecan.British Journal of Pharmacology (2001) 132 , 73–84; doi: 10.1038/sj.bjp.0703766