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


CONCLUSIONS
The 830C>G SNP of CES2 is unlikely to have significant functional consequences on CES2 expression, activity or function.
Bellott
Ricardo
R
Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié, Université Victor Segalen Bordeaux 2, France.
Le Morvan
Valérie
V
Charasson
Virginie
V
Laurand
Armelle
A
Colotte
Marthe
M
Zanger
Ulrich M
UM
Klein
Kathrin
K
Smith
Denis
D
Bonnet
Jacques
J
Robert
Jacques
J
D000483:Alleles; D019943:Amino Acid Substitution; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D043182:Carboxylesterase / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D004247:DNA / Q000235:genetics; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000737:chemistry; D016612:Paraffin Embedding; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D004247:DNA; C517204:CES2 protein, human; D043182:Carboxylesterase; D002166:Camptothecin