• 1
    Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 10417.
  • 2
    Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 90514.
  • 3
    Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 22937.
  • 4
    Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51: 418791.
  • 5
    Iyer L, King CD, Whitington PF et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998; 101: 84754.
  • 6
    Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998; 95: 81704.
  • 7
    Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C. Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002; 62: 60817.
  • 8
    Yamanaka H, Nakajima M, Katoh M et al. A novel polymorphism in the promoter region of human UGT1A9 gene (UGT1A9*22) and its effects on the transcriptional activity. Pharmacogenetics 2004; 14: 32932.
  • 9
    Cecchin E, Innocenti F, D'Andrea M et al. Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 2009; 27: 245765.
  • 10
    Ando M, Ando Y, Sekido Y, Ando M, Shimokata K, Hasegawa Y. Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese cancer patients. Jpn J Cancer Res 2002; 93: 5917.
  • 11
    Fujita K, Ando Y, Nagashima F et al. Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer. Cancer Chemother Pharmacol 2007; 60: 51522.
  • 12
    Han JY, Lim HS, Shin ES et al. Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 2006; 24: 223744.
  • 13
    Lankisch TO, Schulz C, Zwingers T et al. Gilbert's Syndrome and irinotecan toxicity: combination with UDP-glucuronosyltransferase 1A7 variants increases risk. Cancer Epidemiol Biomarkers Prev 2008; 17: 695701.
  • 14
    Levesque E, Belanger AS, Harvey M et al. Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens. J Pharmacol Exp Ther 2013; 345: 95101.
  • 15
    Ando Y, Saka H, Ando M et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000; 60: 69216.
  • 16
    Innocenti F, Vokes EE, Ratain MJ. Irinogenetics: what is the right star? J Clin Oncol 2006; 24: 22214.
  • 17
    Okuyama Y, Hazama S, Nozawa H et al. Prospective phase II study of FOLFIRI for mCRC in Japan, including the analysis of UGT1A1 28/6 polymorphisms. Jpn J Clin Oncol 2011; 41: 47782.
  • 18
    Kato T, Okuyama Y, Nagata N et al. Multicenter phase II studies of FOLFIRI with reduced starting dose of irinotecan in metastatic CRC patients with homozygous for UGT1A1*28/*6. Presented at the ASCO Gastrointestinal Cancers Symposium; 1417 Jan 2009, San Francisco, CA.
  • 19
    Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 20516.
  • 20
    The Food and Drug Administration Center for Drug Evaluation and Research held in November 2004. [Cited 21 Jul 2005.] Available from URL:
  • 21
    Hazama S, Nagashima A, Kondo H et al. Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism. Cancer Sci 2010; 101: 7227.
  • 22
    Wang L, Hirayasu K, Ishizawa M, Kobayashi Y. Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. Nucleic Acids Res 1994; 22: 17745.
  • 23
    Kobayashi M, Hazama S, Takahashi K et al. Is there diversity among UGT1A1 polymorphism in Japan? World J Gastrointest Oncol 2011; 4: 1705.
  • 24
    Guillemette C, Ritter JK, Auyeung DJ, Kessler FK, Housman DE. Structural heterogeneity at the UDP-glucuronosyltransferase 1 locus: functional consequences of three novel missense mutations in the human UGT1A7 gene. Pharmacogenetics 2000; 10: 62944.
  • 25
    The R Project for Statistical Computing. [Cited 20 May 2013.] Available from URL:
  • 26
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 2635.
  • 27
    Akiyama Y, Fujita K, Nagashima F et al. Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy. Ann Oncol 2008; 19: 208990.
  • 28
    Innocenti F, Undevia SD, Iyer L et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22: 13828.
  • 29
    Satoh T, Ura T, Yamada Y et al. Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci 2011; 102: 186873.
  • 30
    Martinez-Balibrea E, Abad A, Martinez-Cardus A et al. UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy. Br J Cancer 2010; 103: 5819.