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The Anticancer Prodrug CPT-11 Is a Potent Inhibitor of Acetylcholinesterase but Is Rapidly Catalyzed to SN-38 by Butyrylcholinesterase¹

Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [C. L. M., M. K. D., P. M. P.]; and Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78245 [R. M. W.]

Patients treated with high doses of CPT-11 rapidly develop a cholinergic syndrome that can be alleviated by atropine. Although CPT-11 was not a substrate for acetylcholinesterase (AcChE), in vitro assays confirmed that CPT-11 inhibited both human and electric eel AcChE with apparent K_is of 415 and 194 nM, respectively. In contrast, human or equine butyrylcholinesterase (BuChE) converted CPT-11 to SN-38 with K_ms of 42.4 and 44.2 µM for the human and horse BuChE, respectively. Modeling of CPT-11 within the predicted active site of AcChE and BuChE corroborated experimental results indicating that, although the drug was oriented correctly for activation, the constraints dictated by the active site gorge were such that CPT-11 would be unlikely to be activated by AcChE.

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