PMID- 18173233
OWN - NLM
STAT- MEDLINE
DCOM- 20080417
LR  - 20220110
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 51
IP  - 2
DP  - 2008 Jan 24
TI  - Identification of human intestinal carboxylesterase as the primary enzyme for 
      activation of a doxazolidine carbamate prodrug.
PG  - 298-304
LID - 10.1021/jm7011479 [doi]
AB  - Doxazolidine (Doxaz), a formaldehyde-doxorubicin (Dox) conjugate, exhibits 
      markedly increased tumor toxicity with respect to Dox without a concurrent 
      increase in toxicity to cardiomyocytes. Pentyl PABC-Doxaz (PPD) is a Doxaz 
      carbamate prodrug that is hydrolyzed by carboxylesterases. Here, we identify 
      human intestinal carboxylesterase (hiCE) as the agent of activation for PPD. Upon 
      prodrug treatment, cells that express higher levels of hiCE responded with lower 
      IC50 values for growth inhibition. Exposing MCF-7 human breast cancer cells, 
      which respond poorly and express little hiCE, to PPD together with hiCE resulted 
      in a dramatic decrease in the IC50, a decrease that was absent when human 
      carboxylesterase 1 was added to prodrug treatment. Finally, U373MG glioblastoma 
      cells overexpressing hiCE displayed approximately 100-fold reduction in the IC50 
      for PPD compared to cells lacking the carboxylesterase. Overall, our studies 
      indicate that PPD is selectively hydrolyzed to the active metabolite by hiCE.
FAU - Barthel, Benjamin L
AU  - Barthel BL
AD  - Department of Chemistry and Biochemistry, University of Colorado, Boulder, 
      Colorado 80309-0215, USA.
FAU - Torres, Renee C
AU  - Torres RC
FAU - Hyatt, Janice L
AU  - Hyatt JL
FAU - Edwards, Carol C
AU  - Edwards CC
FAU - Hatfield, M Jason
AU  - Hatfield MJ
FAU - Potter, Philip M
AU  - Potter PM
FAU - Koch, Tad H
AU  - Koch TH
LA  - eng
GR  - CA76202/CA/NCI NIH HHS/United States
GR  - T32 GM008759/GM/NIGMS NIH HHS/United States
GR  - T32 GM0088759/GM/NIGMS NIH HHS/United States
GR  - CA108775/CA/NCI NIH HHS/United States
GR  - P30 CA21765/CA/NCI NIH HHS/United States
GR  - T32 GM142607/GM/NIGMS NIH HHS/United States
GR  - CA98468/CA/NCI NIH HHS/United States
GR  - CA79763/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080104
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carbamates)
RN  - 0 (Prodrugs)
RN  - 0 (Recombinant Proteins)
RN  - 0 (pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate)
RN  - 80168379AG (Doxorubicin)
RN  - EC 3.1.1.- (Carboxylic Ester Hydrolases)
RN  - EC 3.1.1.1 (CES1 protein, human)
SB  - IM
MH  - Antineoplastic Agents/*metabolism/pharmacology
MH  - Carbamates/*metabolism/pharmacology
MH  - Carboxylic Ester Hydrolases/*metabolism
MH  - Cell Line, Tumor
MH  - Doxorubicin/*analogs & derivatives/metabolism/pharmacology
MH  - Humans
MH  - Intestines/*enzymology
MH  - Prodrugs/*metabolism/pharmacology
MH  - Recombinant Proteins/metabolism
EDAT- 2008/01/05 09:00
MHDA- 2008/04/18 09:00
CRDT- 2008/01/05 09:00
PHST- 2008/01/05 09:00 [pubmed]
PHST- 2008/04/18 09:00 [medline]
PHST- 2008/01/05 09:00 [entrez]
AID - 10.1021/jm7011479 [doi]
PST - ppublish
SO  - J Med Chem. 2008 Jan 24;51(2):298-304. doi: 10.1021/jm7011479. Epub 2008 Jan 4.