Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan

1 This study investigates the mechanisms accounting for the adverse choline rgic effects of the antitumour drug irinotecan. The activity of irinotecan and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), was ass ayed in models suitable for pharmacological studies on cholinergic system. 2 Irinotecan moderately inhibited human or electric eel acetylcholinesteras e activity, SN-38 had no effect, whereas physostigmine blocked both the enz ymes with high potency and efficacy. 3 Irinotecan and SN-38 did not affect spontaneous or electrically-induced c ontractile activity of human colonic muscle. Acetylcholine and dimethylphen ylpiperazinium (DMPP) caused phasic contractions or relaxations, respective ly. Physostigmine enhanced the motor responses elicited by electrical stimu lation. 4 Although irinotecan and SN-38 did not modify the basal contractile activi ty of guinea-pig ileum longitudinal muscle strips, irinotecan 100 muM moder ately enhanced cholinergic twitch contractions. Acetylcholine or DMPP cause d phasic contractions, whereas physostigmine enhanced the twitch responses. Electrically-induced [H-3]-acetylcholine release was reduced by irinotecan (100 muM) or physostigmine (0.1 muM). 5 Intravenous irinotecan stimulated gastric acid secretion in rats, but no effects were obtained with SN-38, physostigmine or i.c.v. irinotecan. Hyper secretion induced by irinotecan was partly prevented by ondansetron, and un affected by capsazepine. In the presence of atropine, vagotomy and systemic or vagal ablation of capsaicin-sensitive afferent fibres, irinotecan did n ot stimulate gastric secretion. 6 The present results indicate that irinotecan and SN-38 do not act as spec ific acetylcholinesterase blockers or acetylcholine receptor agonists. It i s rather suggested that irinotecan promotes a parasympathetic discharge to peripheral organs, mediated by capsaicin-sensitive vagal afferent fibres, a nd that serotonin 5-HT3 receptors are implicated in the genesis of vago-vag al reflex triggered by irinotecan.