Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and Irinotecan toxicity

Kitagawa, Chiyoe; Ando, Moriaki; Ando, Yoji; Sekido, Y.; Usui, Mikio; Takahashi, Katsuroku; Shimokata, Keiko; Hasegawa, Yuya

doi:10.1200/jco.2004.22.14_suppl.2009

Cited by 6 publications

(3 citation statements)

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“…Depending on the specific variant, these SNPs were successfully analyzed in 154 to 163 patients. The observed frequency of the variant alleles ranged between 0.04 and 0.56, which is in line with relative frequencies reported in Caucasians and Japanese subjects previously 27 , 28 , 29 , 30 , 31 , 32 . In particular, relative frequencies of the variant alleles of ABCC2 −24C>T, ABCC2 1249 G>A, and ABCC2 3972 C>T were comparable, although different distributions across different ethic groups cannot be excluded given the relatively small number of patients studied.…”

Section: Resultssupporting

confidence: 85%

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Jong

Scott-Horton

Kroetz

et al. 2007

Clin Pharmacol Ther

161

109

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Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

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Section: Resultssupporting

confidence: 85%

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Jong

Scott-Horton

Kroetz

et al. 2007

Clin Pharmacol Ther

161

109

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“…In addition to UGT1A1, UGT1A9 and UGT1A7 are responsible for glucuronidation of SN-38, and ATP-binding cassette (ABC) gene products, including ABCB1 (P-glycoprotein), ABCC2 (multidrug resistance-associated protein 2), and ABCG2 (breast cancer-resistance protein) are involved in an elimination pathways of irinotecan [8,41]. However, the additional analyses in the Japanese study found no significant associations between the variants of UGT1A7 or ABCC2 genes and severe adverse reactions [42,43]. Recently, UGT1A9 polymorphisms (UGT1A9 * 5 and UGT1A9 * 3) have been studied in 94 Caucasian patients treated with irinotecan [44].…”

Section: Additional Factors Affecting a Clinical Importance Of Ugt1a1mentioning

confidence: 96%

Pharmacogenetics of irinotecan: A promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan

2005

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This review focuses on a pharmacogenetic association between genetic polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan. Although many studies used pharmacokinetic parameters as surrogate measures for predicting clinical outcomes of irinotecan chemotherapy, they have not produced consistent evidence. On the other hand, genotyping results of UGT1A1 gene appear to predict severe adverse reactions more straightforward than the pharmacokinetic parameters or the phenotypes of the enzymatic activity. A case-control study of Japanese cancer patients revealed that those with the variant UGT1A1 alleles were at significantly higher risk of severe adverse reactions to irinotecan, suggesting that the genotyping strategy would be clinically useful. Nevertheless, clinical importance of the pharmacogenetic testing should differ for different patient groups and for different clinical situations. We need to keep this issue in mind in applying the pharmacogenetic evidence in clinical practice.

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“…The newly developed method for detecting UGT1A1 polymorphisms is feasible and has the potential to be widely used for rapid and accurate screening before irinotecan treatment. There are a number of critical steps that must be considered in strategies for drug disposition and genetic variation, not only in drug-metabolizing enzymes, but also in transporter proteins of absorption and excretion of target drugs (e.g., ATP-binding cassette transporter family and organic anion transporting polypeptide family) [39,40]. The irinotecan/UGT1A1/Invader issue is only the beginning of the development of molecular predictors and genetic techniques to avoid the toxicity risks of cancer treatment.…”

Section: Expert Commentarymentioning

confidence: 99%

Screening for adverse reactions to irinotecan treatment using the Invader^®UGT1A1Molecular Assay

Hasegawa¹,

Ando²,

Shimokata³

2006

Expert Review of Molecular Diagnostics

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Accumulating evidence provides support for the idea that determination of UGT1A1 polymorphisms before irinotecan (CPT-11) treatment is clinically useful and important for predicting and avoiding related toxicities. In 2005, the irinotecan label was updated in the USA in order to provide pharmacogenetic information. A dose reduction of irinotecan should be considered for patients known to be homozygous for the UGT1A1*28 allele when administered in combination with other agents or as a single agent. The feasibility of genotyping for DNA polymorphisms prior to treatment depends on the availability of rapid, accurate and efficient genotyping methods. Genotyping of UGT1A1*28, *6 and *27 by the newly developed Invader UGT1A1 Molecular Assay agreed completely with the genotyping results obtained with established methods, and this molecular assay provides rapid detection of polymorphisms. This newly developed method for detecting UGT1A1 polymorphisms is feasible and has the potential to be widely used for rapid and accurate screening before irinotecan treatment.

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Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and Irinotecan toxicity

Cited by 6 publications

References 0 publications

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Pharmacogenetics of irinotecan: A promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan

Screening for adverse reactions to irinotecan treatment using the Invader^®UGT1A1Molecular Assay

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Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and Irinotecan toxicity

Cited by 6 publications

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Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Pharmacogenetics of irinotecan: A promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan

Screening for adverse reactions to irinotecan treatment using the Invader®UGT1A1Molecular Assay

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About

Screening for adverse reactions to irinotecan treatment using the Invader^®UGT1A1Molecular Assay