PMID- 15299073
OWN - NLM
STAT- MEDLINE
DCOM- 20050113
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 3
IP  - 8
DP  - 2004 Aug
TI  - Characterization of inhibitors of specific carboxylesterases: development of 
      carboxylesterase inhibitors for translational application.
PG  - 903-9
AB  - Carboxylesterases, expressed at high levels in human liver and intestine, are 
      thought to detoxify xenobiotics. The anticancer prodrug 
      7-ethyl-10-[4-1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) is also 
      metabolized by carboxylesterases to produce the active drug 
      7-ethyl-10-hydroxycamptothecin. Activation of CPT-11 by human intestinal 
      carboxylesterase (hiCE) in the human intestine may contribute to delayed onset 
      diarrhea, a dose-limiting side effect of this drug. The goal of this study was to 
      develop small molecule inhibitors selective for hiCE to circumvent or treat the 
      toxic side effects of CPT-11. A secondary goal was to develop molecules that 
      specifically inhibit activation of CPT-11 by a rabbit liver carboxylesterase 
      (rCE). rCE is the most efficient CPT-11-activating enzyme thus far identified, 
      and this enzyme is being developed for viral-directed enzyme prodrug therapy 
      applications. Based on in vitro assays with partially purified hiCE and rCE 
      proteins and on growth inhibition assays using U373MG human glioma cells 
      transfected to express hiCE or rCE (U373pIREShiCE or U373pIRESrCE), we identified 
      specific inhibitors of each enzyme. Lead compounds are derivatives of nitrophenol 
      having 4-(furan-2-carbonyl)-piperazine-1-carboxylic acid or 
      4-[(4-chlorophenyl)-phenylmethyl]-piperazine-1-carboxylic acid substitutions in 
      the p position. Kinetic analysis of each compound for hiCE compared with rCE 
      showed that the Ki values of the most selective of these inhibitors differed by 
      6- to 10-fold. In growth inhibition assays, nontoxic, low micromolar 
      concentrations of these inhibitors increased the EC50 of CPT-11 for U373pIREShiCE 
      or U373pIRESrCE cells by 13- to >1,500-fold. The four compounds characterized in 
      this study will serve as lead compounds for a series of inhibitors to be 
      constructed using a combinatorial approach.
FAU - Yoon, Kyoung Jin P
AU  - Yoon KJ
AD  - Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 
      North Lauderdale, Memphis, TN 3810, USA.
FAU - Hyatt, Janice L
AU  - Hyatt JL
FAU - Morton, Christopher L
AU  - Morton CL
FAU - Lee, Richard E
AU  - Lee RE
FAU - Potter, Philip M
AU  - Potter PM
FAU - Danks, Mary K
AU  - Danks MK
LA  - eng
GR  - CA21765/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Nitrophenols)
RN  - 0 (Recombinant Proteins)
RN  - 7673326042 (Irinotecan)
RN  - 9Z01632KRV (10-hydroxycamptothecin)
RN  - EC 3.1.1.- (Carboxylic Ester Hydrolases)
RN  - EC 3.1.1.1 (Carboxylesterase)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Camptothecin/*analogs & derivatives/*pharmacology
MH  - Carboxylesterase/chemistry
MH  - Carboxylic Ester Hydrolases/*antagonists & inhibitors/chemistry
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Intestinal Mucosa/metabolism
MH  - Irinotecan
MH  - Kinetics
MH  - Liver/enzymology
MH  - Models, Chemical
MH  - Nitrophenols/chemistry
MH  - Protein Biosynthesis
MH  - Rabbits
MH  - Recombinant Proteins/chemistry
MH  - Transfection
EDAT- 2004/08/10 05:00
MHDA- 2005/01/14 09:00
CRDT- 2004/08/10 05:00
PHST- 2004/08/10 05:00 [pubmed]
PHST- 2005/01/14 09:00 [medline]
PHST- 2004/08/10 05:00 [entrez]
AID - 3/8/903 [pii]
PST - ppublish
SO  - Mol Cancer Ther. 2004 Aug;3(8):903-9.