Importance of UDP-glucuronosyltransferase 1A1∗6 for irinotecan toxicities in Japanese cancer patients

Sai, Kimie; Saito, Yoshiro; Sanada, Hiromi; Shirao, Kuniaki; Kurose, Koichi; Saeki, Mayumi; Ozawa, Shogo; Kaniwa, Nahoko; Hirohashi, Setsuo; Saijo, Nagahiro; Sawada, Jun‐ichi; Yoshida, Teruhiko

doi:10.1016/j.canlet.2007.11.009

Cited by 42 publications

(22 citation statements)

References 18 publications

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“…A previous report described the significant increase in the basal level of serum total bilirubin in UGT1A1*28 or UGT1A1*6 patients [20]. In our cases, serum total bilirubin was significantly higher in non-wild-type patients compared with wild-type cases, but the levels did not exceed the upper limit of normal.…”

Section: Discussionmentioning

confidence: 45%

“…Han et al [19] first reported that the UGT1A1*6 genotype was related with lower SN-38 glucuronidation and a higher frequency of grade 3–4 toxicities in Korean patients who were treated with the irinotecan-cisplatin combination. Sai et al [20] also documented that the incidence of grade 3/4 neutropenia was significantly higher in patients with the UGT1A1*6 genotype who were treated with irinotecan-based chemotherapy. In line with these observations, the present study revealed a significant association of UGT1A1*6 not only with hematological toxicity but also with life-threatening diarrhea.…”

Section: Discussionmentioning

confidence: 99%

“…Both UGT1A1*6, a G→A transition at codon 71 (G71R), and UGT1A1*27, a C→A transition at codon 229 (P229Q), are polymorphisms of the UGT1A1 gene located on exon 1 [16] and related with reduced SN-38 glucuronidation activity [17, 18]. Recently, a significant association between UGT1A1*6 and severe adverse effects following irinotecan-based chemotherapy has been reported [19, 20]. …”

Section: Introductionmentioning

confidence: 99%

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Clinical Significance of UDP-Glucuronosyltransferase 1A1*6 for Toxicities of Combination Chemotherapy with Irinotecan and Cisplatin in Gynecologic Cancers

et al. 2009

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Background: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. Methods: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m² of irinotecan on days 1, 8 and 15, and 60 mg/m² of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. Results: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. Conclusion: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

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Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical Significance of UDP-Glucuronosyltransferase 1A1*6 for Toxicities of Combination Chemotherapy with Irinotecan and Cisplatin in Gynecologic Cancers

et al. 2009

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“…Irinotecan is an anticancer drug that is widely used in the treatment of different cancers like colorectal and lung cancers [1,2]. The UGT1A1 enzymes are a superfamily of enzymes that are involved in the metabolism of irinotecan.…”

Section: Discussionmentioning

confidence: 99%

“…The prodrug irinotecan is an active anticancer agent for the treatment of a large range of malignancies, including colorectal, lung and gastric cancers through inhibition of topoisomerase I [1,2,3,4]. In 2005, the US Food and Drug Administration (FDA) approved irinotecan as a pharmacogenetic drug [5].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of the UGT1A1*6 (c.211G>A) Polymorphism and Prediction of Irinotecan Toxicity in Iranian Populations of Different Ethnicities

et al. 2014

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Background: Pharmacogenetic studies on irinotecan treatment in patients with metastatic colorectal cancer have indicated that genetic polymorphisms in UGT1A1*6 can lead to decreased enzyme activity and accumulation of the toxic metabolite SN-38. Here, we compared the prevalence of UGT1A1*6 in an Iranian population of different ethnicities with those of other populations. Materials and Methods: A total of 300 healthy people of different ethnic groups including Persian, Azari, Lure, Kurdish, Arab, Baluch and Caspian in the Iranian population were enrolled. Genotyping of the UGT1A1*6 alleles (G/G, A/G, A/A) was performed by polymerase chain reaction-restriction fragment length polymorphism and direct genomic DNA sequencing. Result: The most predictive genotype among the Iranian ethnic groups, especially Persian, was the G/G genotype (wild-type genotype). The frequency of the A/G genotype among the Persian, Azari, Lure, Kurdish, Arab, Baluch and Caspian ethnicities were 15.69% (n = 27), 11.11% (n = 8), 5.88% (n = 1), 9.09% (n = 1), 10% (n = 1), 20% (n = 1) and 0% (n = 0), respectively. Only one person with Persian ethnicity was homozygous for the mutation in UGT1A1*6 (0.58%). Additionally, the frequency of the A and G alleles in Iranians was 6.83 and 93.16%, respectively. Conclusion: The identification of the UGT1A1*6 alleles is necessary among the different Iranian ethnic groups before irinotecan therapy, suggesting that genotyping would be helpful for clinicians to optimize chemotherapy or identify individuals at risk of adverse drug reactions before clinical trials.

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Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Dalvie

Loi

2012

Encyclopedia of Drug Metabolism and Interactions

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Uridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.

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Importance of UDP-glucuronosyltransferase 1A1∗6 for irinotecan toxicities in Japanese cancer patients

Cited by 42 publications

References 18 publications

Clinical Significance of UDP-Glucuronosyltransferase 1A1*6 for Toxicities of Combination Chemotherapy with Irinotecan and Cisplatin in Gynecologic Cancers

Clinical Significance of UDP-Glucuronosyltransferase 1A1*6 for Toxicities of Combination Chemotherapy with Irinotecan and Cisplatin in Gynecologic Cancers

Prevalence of the UGT1A1*6 (c.211G>A) Polymorphism and Prediction of Irinotecan Toxicity in Iranian Populations of Different Ethnicities

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

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