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.
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Acknowledgements
This study was supported by the Ligue Nationale contre le Cancer, comité de la Charente Maritime. We are grateful to Dr S. Mathoulin-Pélissier and Mrs Véronique Brouste, from the Clinical Research Unit of Institut Bergonié, for their help in statistical analysis of the data.
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Bellott, R., Le Morvan, V., Charasson, V. et al. Functional study of the 830C>G polymorphism of the human carboxylesterase 2 gene. Cancer Chemother Pharmacol 61, 481–488 (2008). https://doi.org/10.1007/s00280-007-0493-9
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DOI: https://doi.org/10.1007/s00280-007-0493-9