UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity

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Publication Type Journal Article
School or College College of Social & Behavioral Science
Department Sociology
Creator Wen, Ming
Other Author Iyer, L.; Das, S.; Janisch, L.; Ramírez, J.; Karrison, T.; Fleming, G. F.; Vokes, E. E.; Schilsky, R. L.; Ratain, M. J.
Title UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity
Date 2002
Description The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m−2) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6-45%, 6/7-35% and 7/7-20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.
Type Text
Publisher Wolters Kluwer (LWW)
Volume 2
Issue 1
First Page 43
Last Page 47
Subject UGT1A1*28 polymorphism; Irinotecan disposition; Irinotecan toxicity; Glucuronidation; SN-38
Subject LCSH Chemotherapy
Language eng
Bibliographic Citation Iyer, L., Das, S., Janisch, L., Wen, M., Ramírez, J., Karrison, T., Fleming, G. F., Vokes, E. E., Schilsky, R. L., & Ratain, M. J. (2002). UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics Journal, 2(1), 43-7.
Rights Management (c) Wolters Kluwer (LWW)
Format Medium application/pdf
Format Extent 105,574 bytes
Identifier ir-main,10999
ARK ark:/87278/s68g942s
Setname ir_uspace
Date Created 2012-06-13
Date Modified 2021-05-06
ID 704921
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