The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase
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...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1999-04, Vol.59 (7), p.1458-1463 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | MORTON, C. L WADKINS, R. M DANKS, M. K POTTER, P. M |
| description | 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. |
| format | Article |
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L ; WADKINS, R. M ; DANKS, M. K ; POTTER, P. M</creator><creatorcontrib>MORTON, C. L ; WADKINS, R. M ; DANKS, M. K ; POTTER, P. M</creatorcontrib><description>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.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 10197614</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>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. 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M</creatorcontrib><title>The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Butyrylcholinesterase - metabolism</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - metabolism</subject><subject>Camptothecin - pharmacology</subject><subject>Chemotherapy</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>COS Cells</subject><subject>Eels</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Pharmacology. 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M</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19990401</creationdate><title>The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase</title><author>MORTON, C. L ; WADKINS, R. M ; DANKS, M. K ; POTTER, P. M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-97a1cd79ca628ee7314da883b0c6b3b092f93d47ce894ce9149f5d35fb597fc83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Butyrylcholinesterase - metabolism</topic><topic>Camptothecin - analogs & derivatives</topic><topic>Camptothecin - metabolism</topic><topic>Camptothecin - pharmacology</topic><topic>Chemotherapy</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>COS Cells</topic><topic>Eels</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MORTON, C. L</creatorcontrib><creatorcontrib>WADKINS, R. M</creatorcontrib><creatorcontrib>DANKS, M. K</creatorcontrib><creatorcontrib>POTTER, P. M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MORTON, C. L</au><au>WADKINS, R. M</au><au>DANKS, M. K</au><au>POTTER, P. M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1999-04-01</date><risdate>1999</risdate><volume>59</volume><issue>7</issue><spage>1458</spage><epage>1463</epage><pages>1458-1463</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>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.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>10197614</pmid><tpages>6</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 1999-04, Vol.59 (7), p.1458-1463 |
| issn | 0008-5472 1538-7445 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| 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 |
| title | The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase |
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