Régulation de l'inactivation intratumorale de l'agent antinéoplasique irinotécan par un mécanisme épigénétique

by Gagnon, Jean-François

UGT1A1 is the main enzyme involved in the hepatic and tumoral inactivation of SN-38, an

anticancer agent used in first line treatment of metastasic colorectal cancer. UGT1A1

genetic factors determine response to irinotecan therapy. We hypothesised that an

epigenetic mechanism, more specifically methylation, is involved in tumoral regulation of

UGT1A1 levels. Specific CpG islands in the UGT1A1 gene are hypermethylated and linked

to the repression of gene expression and to lower levels of SN-38 glucuronidation in colon

tumor cells in vitro. In addition, methylation of specific CpG was linked to lower

expression of UGT1A1 gene in primary colon tumors from patients. Our data support that

methylation profile of the UGT1A1 gene determine SN-38 tumoral concentration and may

help to predict tumoral response to irinotecan.