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- Publisher Website: 10.1038/sj.tpj.6500072
- Scopus: eid_2-s2.0-0036025450
- PMID: 11990381
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Article: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity
Title | UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity |
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Authors | |
Keywords | Glucuronidation Irinotecan Polymorphism SN-38 UGT1A1 |
Issue Date | 2002 |
Citation | Pharmacogenomics Journal, 2002, v. 2, n. 1, p. 43-47 How to Cite? |
Abstract | 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 UGT1AI 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 (616>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. |
Persistent Identifier | http://hdl.handle.net/10722/323766 |
ISSN | 2023 Impact Factor: 2.9 2023 SCImago Journal Rankings: 0.659 |
DC Field | Value | Language |
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dc.contributor.author | Iyer, L. | - |
dc.contributor.author | Das, S. | - |
dc.contributor.author | Janisch, L. | - |
dc.contributor.author | Wen, M. | - |
dc.contributor.author | Ramírez, J. | - |
dc.contributor.author | Karrison, T. | - |
dc.contributor.author | Fleming, G. F. | - |
dc.contributor.author | Vokes, E. E. | - |
dc.contributor.author | Schilsky, R. L. | - |
dc.contributor.author | Ratain, M. J. | - |
dc.date.accessioned | 2023-01-13T02:59:12Z | - |
dc.date.available | 2023-01-13T02:59:12Z | - |
dc.date.issued | 2002 | - |
dc.identifier.citation | Pharmacogenomics Journal, 2002, v. 2, n. 1, p. 43-47 | - |
dc.identifier.issn | 1470-269X | - |
dc.identifier.uri | http://hdl.handle.net/10722/323766 | - |
dc.description.abstract | 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 UGT1AI 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 (616>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. | - |
dc.language | eng | - |
dc.relation.ispartof | Pharmacogenomics Journal | - |
dc.subject | Glucuronidation | - |
dc.subject | Irinotecan | - |
dc.subject | Polymorphism | - |
dc.subject | SN-38 | - |
dc.subject | UGT1A1 | - |
dc.title | UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1038/sj.tpj.6500072 | - |
dc.identifier.pmid | 11990381 | - |
dc.identifier.scopus | eid_2-s2.0-0036025450 | - |
dc.identifier.volume | 2 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | 43 | - |
dc.identifier.epage | 47 | - |