Disease relevance of CES2

• PURPOSE: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity [1].
• Eight of 23 high CES2 mRNA-expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071) [1].
• Among the 18 types of tumors analyzed, 2 types (gallbladder tumor and lymphoma) did not express CES2, 5 types expressed weak CES2, and 11 types expressed moderate to intense CES2 [2].
• PURPOSE: Irinotecan, a drug widely used in the treatment of advanced colorectal cancers, is a prodrug requiring activation to 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase 2 (hCE2) [3].
• Altered expression of TFF-1 and CES-2 in Barrett's Esophagus and associated adenocarcinomas [4].

High impact information on CES2

• A single cDNA insert (designated CE2) of 2153 base pairs (bp) contains an open reading frame of 836 bp, which is incomplete at its 5' end [5].
• A 259-base pair fragment of the FCAR promoter is sufficient to direct myeloid expression of a reporter gene and contains functionally important binding sites for CCAAT/enhancer-binding protein alpha (C/EBPalpha) (CE1, CE2, and CE3) and an unidentified Ets-like nuclear protein [6].
• Taken together, we suggest that CTM alleviates repression by CE2, which allows HSF to be heat-inducibly phosphorylated and presume that phosphorylation is a prerequisite for the activator function of HSF when it binds to an atypical HSE [7].
• Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2 [8].
• However, strong LATI was elicited when these injections were performed in mice challenged with tumor cells admixed at 1/10 cell ratio with nonreactive lymphocytes from CE-2-bearing mice [9].

Biological context of CES2

• However, we did not observe significant differences in CES2 activities (irinotecan and procaine hydrolysis) among individuals with different haplotypes [10].
• In the present study, to investigate the transcriptional regulation of the promoter region of the CES1 and CES2 genes were isolated from mouse, rat and human genomic DNA by PCR amplification [11].
• Twelve novel single nucleotide polymorphisms (SNPs) were found in the CES2 gene from 153 Japanese individuals, who were administered irinotecan or steroidal drugs [12].
• 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 [13].
• Relative CES1 and CES2 expression levels were determined by reverse transcription of the respective mRNAs, followed by polymerase chain reaction amplification [14].

Anatomical context of CES2

• There are two known carboxylesterases expressed in human liver, small intestine and other tissues, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) [10].
• Microsome samples prepared from liver tissues of 78 normal individuals were used to determine the rate of hydrolysis of irinotecan and procaine (an anaesthetic hydrolysed by CES2 but not CES1) [10].
• Hybridization analyses showed that CES2 is highly expressed in the heart, skeletal muscle, colon, spleen, kidney and liver, but considerably less expressed in fetal tissues (e.g. fetal heart, kidney, spleen, and liver) and cancer cells [15].
• Inhibition of CES2 in the gastrointestinal tract by loperamide may reduce local formation of 5'-DFCR [16].
• Expression of the carboxylesterase gene CES2 was comparable in the two cell lines and much higher than CES1 gene expression [17].

Associations of CES2 with chemical compounds

• Pentyl 4-(N-doxazolidinylcarbonyloxymethyl)phenylcarbamate, the lead compound for further investigation, appears to be activated in Hep G2 cells that express both CES1 and CES2 [14].
• Loperamide is a strong inhibitor of CES2, with a K(i) of 1.5 muM, but it only weakly inhibits CES1A1 (IC(50) = 0.44 mM) [16].
• CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min(-1) mM(-1), respectively [16].
• CES1 and CES2 mRNA levels after exposure to 50 microM NO-1886 were significantly increased by 1.4 (p<0.05) and 2.6 times (p<0.01), respectively, compared with untreated controls [18].
• A human liver carboxylesterase (hCE-2) that catalyzes the hydrolysis of the benzoyl group of cocaine and the acetyl groups of 4-methylumbelliferyl acetate, heroin, and 6-monoacetylmorphine was purified from human liver [19].

Other interactions of CES2

• The distal promoter is active in both orientations, suggesting its potential role in the transcription of another gene, CGI-128, located immediately upstream to the distal promoter in the opposite direction with respect to CES2 [15].
• METHODS: In a series of 115 human deoxyribonucleic acid samples, we have explored the 12 exons of the hCE2 gene, the intron-exon junctions, and the 5'- and 3'-untranslated regions, by denaturing HPLC and sequencing of polymerase chain reaction products [3].
• All three enzymes rapidly catalyzed hydrolysis of heroin to 6-monoacetylmorphine (hCE-1 kcat = 439 min-1, hCE-2 kcat = 2186 min-1 and pseudocholinesterase kcat = 13 min-1) [20].

Analytical, diagnostic and therapeutic context of CES2

• Northern blot analysis indicates that relative expression in intestinal tissue is CES2 > CES1A1 > CES3 [16].
• Tumor CES2 expression may contribute to variable response to irinotecan chemotherapy for solid tumors [2].
• The expression profile of CES2 protein in human tumor tissues was evaluated in a tissue array of 18 different types of human cancer and in a panel of normal human liver samples by immunohistochemistry and Western blot, respectively [2].
• The functionality of the variations identified was studied in 60 human liver samples by measuring hCE2 gene expression by real-time reverse transcriptase-polymerase chain reaction of messenger ribonucleic acid extracts and carboxylesterase activity by use of irinotecan as a substrate [3].
• Sequence analysis of the cloned transcripts revealed that IVS8-2A>G yielded mostly aberrantly spliced transcripts, including a deleted exon or a 32-bp deletion proximal to the 5' end of exon 9, which resulted in truncated hCE-2 proteins [21].

References