Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11.
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.
Hyatt
Janice L
JL
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Tsurkan
Lyudmila
L
Morton
Christopher L
CL
Yoon
Kyoung J P
KJ
Harel
Michal
M
Brumshtein
Boris
B
Silman
Israel
I
Sussman
Joel L
JL
Wadkins
Randy M
RM
Potter
Philip M
PM
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
D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D000077146:Irinotecan; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002166:Camptothecin