Modifications of human carboxylesterase for improved prodrug activation.
BACKGROUND
Carboxylesterases (CEs) are ubiquitous enzymes responsible for the hydrolysis of numerous clinically useful drugs. As ester moieties are frequently included in molecules to improve their water solubility and bioavailability, de facto they become substrates for CEs.


OBJECTIVE
In this review, we describe the properties of human CEs with regard to their ability to activate anticancer prodrugs and demonstrate how structure-based design can be used to modulate substrate specificity and to increase efficiency of hydrolysis.


METHODS
A specific example using CPT-11 and a human liver CE is discussed. However, these techniques can be applied to other enzymes and their associated prodrugs.


RESULTS
Structure-guided mutagenesis of CEs can be employed to alter substrate specificity and generate novel enzymes that are efficacious at anticancer prodrug activation.
Hatfield
Jason M
JM
Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Wierdl
Monika
M
Wadkins
Randy M
RM
Potter
Philip M
PM
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology; D016296:Mutagenesis; D011355:Prodrugs / Q000493:pharmacokinetics*; D012995:Solubility
D000970:Antineoplastic Agents; D011355:Prodrugs; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin