Kitagawa_2004_J.Clin.Oncol_22_2009

2009 Background: Irinotecan unexpectedly causes severe, occasionally fatal, toxicity of leukopenia or diarrhea. Irinotecan is metabolized by carboxylesterase to form an active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 to yield its b-glucuronide. Multidrug resistance-assocciated protein 2 (MRP2, ABCC2) transports SN-38-glucuronide from hepatocytes to the bile, as it transports bilirubin in the body.
METHODS: We examined the polymorphisms of ABCC2 gene, -24C>T, 1249G>A, 2366C>T, 2302C>T, 2375A>G, 2439+2 T>C, 3449 G>A, and 3517A>T, in 120 Japanese cancer patients who had been treated with irinotecan, including 27 patients who experienced severe toxicity of G4 leukopenia and/or G3 or worse diarrhea. Our hypothesis was that patients with the variant ABCC2 allele would have an increased risk of severe toxicity.
RESULTS: We detected the four variant alleles, -24C>T, 1249G>A, 2366C>T, and 2375A>G. The association between ABCC2 variants, -24C>T or 1249G>A, and severe toxicity was investigated (Table). Neither univariate analysis (odds ratio, 0.78; 95% confidential interval (CI), 0.21-2.35; odds ratio, 1.05; 95% CI, 0.41-2.56) nor multivariate logistic regression analysis (odds ratio, 0.98; 95% CI, 0.23-3.44; odds ratio, 1.17; 95% CI, 0.40-3.26) found any significant association between severe toxicity and the ABCC2 variants in 1249G>A or -24C>T, respectively. We detected a heterozygote for 2366C>T in one patient and a new heterozygote for 2375A>G in one patient. Severe toxicity was not occurred in these patients. There were no apparent associations between the ABCC2 variants and pharmacokinetics of irinotecan, SN-38 and SN-38 glucuronide.
CONCLUSIONS: This pharmacogenetic study did not find any evidence that determination of ABCC2 genotypes would be useful for predicting severe toxicity by irinotecan. [Figure: see text] No significant financial relationships to disclose.