Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11

Academic Article


  • 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. © 2005 Elsevier Ireland Ltd. All rights reserved.
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    Digital Object Identifier (doi)

    Author List

  • Hyatt JL; Tsurkan L; Morton CL; Yoon KJP; Harel M; Brumshtein B; Silman I; Sussman JL; Wadkins RM; Potter PM
  • Start Page

  • 247
  • End Page

  • 252
  • Volume

  • 157-158