The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 7; pp. 1458 - 1463
• Main Authors: MORTON, C. L, WADKINS, R. M, DANKS, M. K, POTTER, P. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-1999
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Binding Sites; Biological and medical sciences; Butyrylcholinesterase - metabolism; Camptothecin - analogs & derivatives; Camptothecin - metabolism; Camptothecin - pharmacology; Chemotherapy; Cholinesterase Inhibitors - pharmacology; COS Cells; Eels; Humans; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Prodrugs - pharmacology; Antineoplastic agent; Biological fluid; Esterases; Acetylcholinesterase; Blood plasma; Bioreductive drug; Horse; Molecular model; Ungulata; Human; Enzyme; Rodentia; Enzyme inhibitor; Prodrug; Metabolism; Cholinesterase; Carboxylic ester hydrolases; Irinotecan; Vertebrata; Mammalia; Mouse; Animal; Hydrolases; Perissodactyla; Pharmacokinetics
• ISSN: 0008-5472; 1538-7445

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(i)s of 415 and 194 nM, respectively. In contrast, human or equine butyryl-cholinesterase (BuChE) converted CPT-11 to SN-38 with K(m)s of 42.4 and 44.2 microM 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.