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Carboxylesterases expressed in human colon tumor tissue and their role in CPT-11 hydrolysis.

AbstractPURPOSE:
The purpose is to develop new analytical methods to study the expression profile of CPT-11 carboxylesterases and topoisomerase I in colon tumor samples and understand the impact of their expression on CPT-11 metabolism in chemotherapy.
EXPERIMENTAL DESIGN:
We investigated 24 colon tumors for expression of carboxylesterases CES1A1, CES2, CES3, hBr-3, and topoisomerase I genes by real-time PCR and correlated the gene expression with activity assays. The relative abundance of the carboxylesterase isoenzymes and topoisomerase I genes was determined by real-time PCR. Activity assays performed on colon tumor extracts included CPT-11 hydrolase, 4-methylumbelliferyl acetate hydrolase, and topoisomerase I activity assays. Additionally, nondenaturing activity gel electrophoresis with activity staining showed the distribution of carboxylesterases.
RESULTS:
We detect the expression of CES1A1, CES2, and CES3 carboxylesterase genes in human colon tumors. We were unable to detect the hBr-3 (also called hCE-3) in human liver, colon, or brain. We find large interindividual variation, >/=150-fold, for both CES1A1 and CES3 genes, 23-fold for CES2, and 66-fold for topoisomerase I. Only CES2 gene expression correlated with the carboxylesterase activity assays (P < 0.01) with CPT-11 and 4-methylumbelliferyl acetate as substrates. Nondenaturing activity gel electrophoresis showed that CES2 was the most predominant activity. Topoisomerase I gene expression significantly correlated with topoisomerase I activity (P < 0.01) in the colon tumors, but interindividual variation was very high.
CONCLUSIONS:
We conclude that CES2 is the most abundant carboxylesterase in colon tumors that is responsible for CPT-11 hydrolysis. This pilot study reinforces the hypothesis that there is a large interindividual variation in expression of carboxylesterases that may contribute to variation in therapeutic outcome and/or toxicity of CPT-11 therapy for colon cancer.
AuthorsSonal P Sanghani, Sara K Quinney, Tyler B Fredenburg, Zejin Sun, Wilhelmina I Davis, Daryl J Murry, Oscar W Cummings, David E Seitz, William F Bosron
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 13 Pg. 4983-91 (Oct 15 2003) ISSN: 1078-0432 [Print] United States
PMID14581373 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Umbelliferones
  • 4-methylumbelliferyl acetate
  • RNA
  • Irinotecan
  • Hydrolases
  • Carboxylic Ester Hydrolases
  • Carboxylesterase
  • DNA Topoisomerases, Type I
  • Camptothecin
Topics
  • Blotting, Northern
  • Blotting, Western
  • Brain (metabolism)
  • Camptothecin (analogs & derivatives, metabolism)
  • Carboxylesterase (metabolism)
  • Carboxylic Ester Hydrolases (biosynthesis, metabolism)
  • Cell Line, Tumor
  • Colon (metabolism)
  • Colonic Neoplasms (enzymology, metabolism)
  • DNA Topoisomerases, Type I (metabolism)
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Humans
  • Hydrolases (metabolism)
  • Hydrolysis
  • Irinotecan
  • Liver (metabolism)
  • Male
  • RNA (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Umbelliferones (metabolism)

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