title: Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11.
abstract: CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is an anticancer prodrug that has been approved for the treatment of colon cancer. It is a member of the camptothecin class of drugs and activation to the active metabolite SN-38, is mediated by carboxylesterases (CE). SN-38 is a potent topoisomerase I poison and is highly effective at killing human tumor cells, with IC50 values in the low nM range. However, upon high dose administration of CPT-11 to cancer patients, a cholinergic syndrome is observed, that can be rapidly ameliorated by atropine. This suggests a direct interaction of the drug or its metabolites with acetylcholinesterase (AChE). Kinetic studies indicated that CPT-11 was primarily responsible for AChE inhibition with the 4-piperidinopiperidine moiety, the major determinant in the loss of enzyme activity. Structural analogs of 4-piperidinopiperidine however, did not inhibit AChE, including a benzyl piperazine derivate of CPT-11. These results suggest that novel anticancer drugs could be synthesized that do not inhibit AChE, or alternatively, that novel AChE inhibitors could be designed based around the camptothecin scaffold.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Tsurkan
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Kyoung J P
authors.initials: KJ
authors.lastname: Yoon
authors.forename: Michal
authors.initials: M
authors.lastname: Harel
authors.forename: Boris
authors.initials: B
authors.lastname: Brumshtein
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
authors.forename: Randy M
authors.initials: RM
authors.lastname: Wadkins
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D000077146:Irinotecan; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002166:Camptothecin