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Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan.
Characterization of a novel mechanism accounting for the adverse cholinergic effects of the anticancer drug irinotecan.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2001 Jan; Vol. 132 (1), pp. 73-84. - Publication Year :
- 2001
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Abstract
- 1. 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. 2. 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. 3. 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. 4. Although irinotecan and SN-38 did not modify the basal contractile activity of guinea-pig ileum longitudinal muscle strips, irinotecan 100 microM 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 microM) or physostigmine (0.1 microM). 5. 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. 6. 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.
- Subjects :
- Acetylcholine metabolism
Acetylcholinesterase metabolism
Animals
Colon drug effects
Colon physiology
Colorimetry
Electric Stimulation
Electrophorus
Enzyme Inhibitors pharmacology
Gastric Acid metabolism
Guinea Pigs
Humans
Ileum drug effects
Ileum innervation
Ileum physiology
In Vitro Techniques
Irinotecan
Male
Muscle Contraction drug effects
Muscle, Smooth drug effects
Muscle, Smooth physiology
Rats
Rats, Wistar
Topoisomerase I Inhibitors
Antineoplastic Agents adverse effects
Camptothecin adverse effects
Camptothecin analogs & derivatives
Parasympathetic Nervous System drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 132
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11156563
- Full Text :
- https://doi.org/10.1038/sj.bjp.0703766