Title : Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11 - Hyatt_2005_Chem.Biol.Interact_157-158_247 |
Author(s) : Hyatt JL , Tsurkan L , Morton CL , Yoon KJ , Harel M , Brumshtein B , Silman I , Sussman JL , Wadkins RM , Potter PM |
Ref : Chemico-Biological Interactions , 157-158 :247 , 2005 |
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. |
PubMedSearch : Hyatt_2005_Chem.Biol.Interact_157-158_247 |
PubMedID: 16257398 |
Inhibitor | Irinotecan |
Hyatt JL, Tsurkan L, Morton CL, Yoon KJ, Harel M, Brumshtein B, Silman I, Sussman JL, Wadkins RM, Potter PM (2005)
Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11
Chemico-Biological Interactions
157-158 :247
Hyatt JL, Tsurkan L, Morton CL, Yoon KJ, Harel M, Brumshtein B, Silman I, Sussman JL, Wadkins RM, Potter PM (2005)
Chemico-Biological Interactions
157-158 :247