Concluding Remarks

Recent research on the haplotype structures covering the UGT1A gene complex has revealed the linkage patterns of the functional polymorphisms within the complex and their large ethnic variations. To date, cumulative data indicate the primary importance of UGT1A1 genetic polymorphisms, in particular the *28 promoter polymorphism, as a risk factor for severe irinotecan toxicities. Therefore, the clinical application of genetic testing for *28 has started in the United States.

Recent haplotype-phenotype studies have also indicated that the genetic relevance to toxic events varies depending on ethnicity and regimen. On this point, it must be noted that 1A1*6 in East-Asians is also an important risk factor for severe neutropenia. In contrast, the effects of UGT1A genotypes on the anti-tumor responses to irinotecan treatment remain unclear. Therefore, further clinical studies are needed to evaluate the benefits of the genotyping of *28 and *6 or other markers in terms of irinotecan efficacy.

In addition to the UGT1A genotypes, the genetic variations of other biomolecules responsible for irinotecan metabolism and disposition, such as ABCB1 (56) and OATP-C (57), should be evaluated for their clinical impact. Information of public databases available in several web sites, such as the ENCODE project data (www.ensembl.org/Homo_sapiens/encode.html) and the Pharmacogenetics and Phar-macogenomics Knowledge Base (PharmaGKB) (www.pharmgkb.org), would facilitate further irinotecan-pharmacogenetic studies. Other diagnostic approaches including transcriptomics, proteomics, and metabolomics would provide additional effective biomarkers to more precisely predict toxic events and anti-tumor responses.

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