Functional study of the 830C>G polymorphism of the human carboxylesterase 2 gene.

Abstract

PURPOSE:

Carboxylesterase 2 (CES2) is involved in the activation of the anticancer drug irinotecan to its active metabolite SN-38. We previously identified a single nucleotide polymorphism (SNP), with an allele frequency around 10%, as possibly involved in enzyme expression (Clin Pharmacol Ther 76:528-535, 2004), which could explain the large individual variation in SN-38 disposition.

METHODS:

The 830C>G SNP, located in the 5' untranslated region of the gene, was analysed in various DNA samples extracted from: (1) the National Cancer Institute NCI-60 panel of human tumour cell lines; (2) a collection of 104 samples of normal tissue from colorectal cancer patients; (3) blood samples from a population of 95 normal subjects; (4) a collection of 285 human livers. CES2 genotypes were tentatively related to irinotecan cytotoxicity and CES2 expression in the NCI-60 panel; to response to treatment and event-free survival in colorectal cancer patients; and to CES2 expression and catalytic activity in subsets of the human liver collection.

RESULTS:

No significant relationship was found in the NCI-60 panel between CES2 830C>G genotype and irinotecan cytotoxicity or CES2 expression. No significant relationship was found between CES2 830C>G genotype and the toxicity and therapeutic efficacy (tumour response, event-free survival) of irinotecan in colorectal cancer patients. There was no significant relationship between CES2 830C>G genotype and CES2 expression and catalytic activity determined in a subset of genotype-selected liver samples.

CONCLUSION:

The 830C>G SNP of CES2 is unlikely to have significant functional consequences on CES2 expression, activity or function.

• Authors: Ricardo Bellott, Valérie Le Morvan, Virginie Charasson, Armelle Laurand, Marthe Colotte, Ulrich M Zanger, Kathrin Klein, Denis Smith, Jacques Bonnet, Jacques Robert
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 61 Issue 3 Pg. 481-8 (Mar 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17483951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Irinotecan
• DNA
• CES2 protein, human
• Carboxylesterase
• Camptothecin

Topics

• Alleles
• Amino Acid Substitution
• Antineoplastic Agents, Phytogenic (pharmacokinetics)
• Camptothecin (analogs & derivatives, pharmacokinetics)
• Carboxylesterase (genetics)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics)
• DNA (genetics)
• Genotype
• Humans
• Irinotecan
• Liver (chemistry)
• Paraffin Embedding
• Polymorphism, Single Nucleotide (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis