Frequency Of UGT1A1 Research Articles

The association between UGT1A1 polymorphisms and treatment toxicities of liposomal irinotecan

Initial dose adjustment is recommended for patients with known UGT1A1∗28 homozygosity for both conventional irinotecan and liposomal irinotecan (nal-IRI). A recent population pharmacokinetic (PK) study showed that Asian patients had a lower prevalence of UGT1A1∗28 homozygosity but a significantly higher maximum blood concentration of SN-38 (SN-38 Cmax) and a higher incidence of grade ≥3 neutropenia after nal-IRI administration than Caucasian patients. The current study investigated the association of UGT1A1 polymorphisms, including the Asian prevalent UGT1A1∗6, PK and toxicities of nal-IRI-based therapy in the Asian population. A total of 162 patients with nal-IRI-based therapy and available UGT1A1∗6 and UGT1A1∗28 genotyping were included, with 82 Asian patients from six previous phase I or II studies of nal-IRI (cohort 1) and another 80 patients with nal-IRI+ 5-fluorouracil/leucovorin every 2 weeks as real-world practice in a single institute in Taiwan (cohort 2). The frequency of UGT1A1∗6 or UGT1A1∗28 homozygosity/compound heterozygosity was 9.3%, with UGT1A1∗6/∗6 in 2.5%, UGT1A1∗28/∗28 in 1.9% and UGT1A1∗6/∗28 in 4.9%. Among the 53 patients in cohort 1 with available PK data, all 7 patients with homozygosity/compound heterozygosity harbored UGT1A1∗6 and had a significantly higher level of median dose-normalized area under the concentration-time curve (AUC) and Cmax of SN-38 than those with single heterozygosity/wild type. Of the entire study population, the incidence of grade ≥3 neutropenia and diarrhea was significantly higher in patients with homozygosity/compound heterozygosity than in those with single heterozygosity/wild type, 73.3% versus 38.1% (P= 0.012, Fisher's exact test) and 33.3% versus 9.5% (P= 0.018, Fisher's exact test), respectively. The results suggest that the recommendation of a lower starting dose of nal-IRI for patients with UGT1A1∗28 homozygosity should be extended to include patients with UGT1A1∗6 homozygosity/compound heterozygosity.

Significance of UGT1A1*28 Genotype in Patients with Advanced Liver Injury Caused By Chronic Hepatitis C.

SummaryBackgroundChronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations in UGT1A1 gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association of UGT1A1 TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse.MethodsGenetic testing of UGT1A1 TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging.ResultsUGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence of UGT1A1*28 genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation of UGT1A1*28 genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence of UGT1A1*28 genotype in CHC patients with severe liver injury.ConclusionsFrequencies of UGT1A1*28 genotype are high in both Serbian CHC patients and healthy subjects. The presence of UGT1A1*28 genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.

Significance of UGT1A1*28 Genotype in Patients with Advanced Liver Injury Caused by Chronic Hepatitis C

SummaryBackground:Chronic hepatitis C (CHC) is a significant cause of liver related morbidity and mortality worldwide. The role of genetics in the host response to hepatitis C virus is not elucidated. Genetic variations inUGT1A1gene are the most common cause of hereditary unconjugated hyperbilirubinemia-Gilbert syndrome. This is the first study investigating the association ofUGT1A1TA repeats promoter genotypes with the degree of liver injury, viremia and biochemical markers in CHC patients with advanced liver injury and late virological relapse.Methods:Genetic testing ofUGT1A1TA repeats promoter genotypes was performed in 42 CHC patients with advanced fibrosis and cirrhosis who achieved sustained virological response and 42 healthy blood donors. CHC patients were evaluated for clinical findings, laboratory tests and imaging.Results:UGT1A1*28 genotype (7/7 TA repeats) was observed in 23.8% CHC patients and 16.7% healthy controls with no significant difference in genotype frequencies (p=0.49). Pretreatment levels of ferritin and bilirubin were associated with the presence ofUGT1A1*28genotype, indicating its potential as a predictive marker. However, in our study, there was no correlation ofUGT1A1*28genotype with the degree of fibrosis or viremia. During antiviral treatment, dose reductions and treatment interruptions, as well as treatment success and occurrence of late virological relapse were not related to the presence ofUGT1A1*28genotype in CHC patients with severe liver injury.Conclusions:Frequencies ofUGT1A1*28genotype are high in both Serbian CHC patients and healthy subjects. The presence ofUGT1A1*28genotype was not associated with ribavirin-related adverse effects and had no effect on long term outcome in CHC patients.

ISY10-4 - Development of new agents for unresectable gastric cancer: Global? Asian? Japanese?

Many clinical trials with new drugs for unresectable gastric cancer has been globally conducted. Although barriers in global development from investigators' point of view do exist, some were overcome and some have been still issues. Drug-specific issues should be considered such as pharmacogenomics evaluation. For example, in Asian populations where the frequency of UGT1A1*28 is low, other UGT1A1 variants can also play a role in irinotecan toxicity: in a Japanese study, two haplotype (*28 containing the UGT1A1*28 allele and *6 containing the exon 1 G71R polymorphism) groups were associated with reduced area under the curve (AUC) ratios of SN-38G to SN-38, which is predicted to have an effect on irinotecan toxicity. Patients with one *6 haplotype and one *28 haplotype had significantly lower AUC ratios compared with patients with homozygous wild-type UGT1A1. Difference in clinical practice has been a common problem when planning global studies. In AVAGAST study, which compared XP vs XP+bevacizumab in the 1st-line setting, HR in OS was 0.63 in Pan-America and 0.97 in Asia. These differences may come from the differences in proportion of 2nd-line treatment and proportion of minimal peritoneal metastasis. Such experiences have been utilized into planning and conducting subsequent global trials in gastric cancer. On the other hand, in Asia, especially in Japan, specific development for patients with peritoneal metastasis have been conducted. Now, however, only patients with severe peritoneal metastasis are excluded from the standard development strategy, there are no conflicts with global development. Totally, Asian trials can be performed without difficulties, and there are some issues to consider to plan and conduct global trials.

Correlation between UGT1A1 polymorphism and neonatal hyperbilirubinemia of neonates in Wuhan.

This study attempts to discuss the correlation between UGT1A1*28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group (case group, n=108) and healthy neonates group (control group, n=60). Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1*28 and Gly71Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that: (1) The frequency of UGT1A1*28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups (P>0.05). (2) The frequency of Gly71Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups (P<0.01). (3) The serum bilirubin level of Gly71Arg mutant homozygous and heterozygous subgroups (n=66) in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup (n=42) (P<0.01). It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1*28 gene polymorphism, but closely with the Gly71Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.

UGT1A1*28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients: Outcomes from a case-control study.

Gilbert syndrome (GS) is a frequent benign clinical condition, marked by intermittent unconjugated hyperbilirubinemia, mostly due to the polymorphism uridine diphosphate-glucuronosyltransferase 1A1∗28 (UGT1A1∗28). Hyperbilirubinemia has been reported in a GS patient undergoing hepatitis C treatment, and other UGT isoforms polymorphisms have been linked to worse outcomes in viral hepatitis. Yet, little is known to GS contributions’ to the liver disease scenario. Our aim was to assess UGT1A1 genotypes’ frequency in chronic hepatitis C (CHC) patients and correlate with total bilirubin (TB). This is a case–control study in a large tertiary medical center. Cases were CHC patients confirmed by hepatitis C virus (HCV)–polymerase chain reaction. Exclusion criteria were hepatitis B virus or human immunodeficiency virus (HIV) coinfection. Control were healthy blood donors. UGT1A1 promoter region gene genotyping was performed, and bilirubin serum levels were available for HCV patients. Genotypes and alleles frequencies were similar in case (n = 585; P = 0.101) and control groups (n = 313; P = 0.795). Total bilirubin increase was noticed according to thymine–adenine repeats in genotypes (P < 0.001), and the TB greater than 1 mg/dL group had more UGT1A1∗28 subjects than in the group with TB values <1 mg/dL (18.3 vs 5.3; P < 0.001). Bilirubin levels are linked to the studied polymorphisms, and this is the first time that these findings are reported in a chronic liver disease sample. Among patients with increased TB levels, the frequency of UGT1A1∗28 is higher than those with normal TB. Personalized care should be considered to GS, regarding either abnormal bilirubin levels or drug metabolism.

UGT1A1 sequence variants associated with risk of adult hyperbilirubinemia: A quantitative analysis

Backgrounds and AimsUDP-glucuronosyltransferase 1 A1 (UGT1A1) is an enzyme that transforms small lipophilic molecules into water-soluble and excretable metabolites. UGT1A1 polymorphisms contribute to hyperbilirubinemia. This study quantitatively associated UGT1A1 variants in patients with hyperbilirubinemia and healthy subjects. MethodsA total of 104 individuals with hyperbilirubinemia and 105 healthy controls were enrolled for genotyping and DNA sequencing UGT1A1 sequence variants, including the Phenobarbital Response enhancer module (PBREM) region, the promoter region (TATA box), and the 5 exons for quantitative association with hyperbilirubinemia. ResultsEleven UGT1A1 variants were revealed in the case and control subjects, four of which were novel coding variants. A variant of PBREM (UGT1A1*60) was found in 47.6% of the patients, a TA repeat motif in the 5-primer promoter region [A(TA)7TAA,UGT1A1*28] was found in 27.9% of the patients, and p.G71R (UGT1A1*6) was in 33.2% of the patients. For the healthy controls, the frequency of UGT1A1*60, UGT1A1*28 and UGT1A1*6 was 26.7%, 9.0% and 15.7%, respectively. Homozygous UGT1A1*28 and homozygous UGT1A1*6 were significantly associated with the risk of adult hyperbilirubinemia, with an odds ratio (OR) of 17.79 (95% CIs, 2.11–133.61) and 14.93 (95% CIs, 1.83–121.88), respectively. Quantitative analysis showed that sense mutation (including UGT1A1*6) and UGT1A1*28/*28, but not UGT1A1*60/*60 or UGT1A1*1/*28, was associated with increased serum total bilirubin (TB) levels. High linkage disequilibrium occurred between UGT1A1*60 and UGT1A1*28 (D′=0.964, r2=0.345). ConclusionsThis study identified four novel UGT1A1 coding variants, some of which were associated with increased serum TB levels. A quantitative approach to evaluate adult hyperbilirubinemia provides a more vigorous framework for better understanding of adult hyperbilirubinemia genetics.

Comprehensive Variant Screening of the UGT Gene Family

PurposeUGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs.Materials and MethodsWe directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs.ResultsA total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation.ConclusionFindings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.

Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai

Background The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai.MethodsOne hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine–adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically.ResultsOne hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ 2 = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ 2 = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction.ConclusionThe (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

A UGT1A1 genotype-directed phase II toxicity and efficacy-finding study of irinotecan combined with S-1 as first-line treatment in advanced gastric cancer.

TPS4154 Background: The best chemotherapy regimen for advanced gastric cancer (AGC) is uncertain, but promising findings have been reported with Irinotecan (IRI) plus S-1. However, IRI can induce severe neutropenia or diarrhea associated with homozygosity of the UGT1A1*28 or UGT1A1*6 alleles. This trial was designed to compare the toxicity and efficacy on different doses of IRI combined with S-1 according to UGT1A1 genotype as first-line chemotherapy in AGC in Chinese patients. Methods: Previously untreated patients with histologically proven gastric or gastroesophageal junction adenocarcinoma, aged between 18 and 75 years with ECOG performance status 0-2 were classified according to UGT1A1 genotype: wild-type (none of *28 or *6 allele); heterozygous (only one of *28 or *6 allele); or homozygous (*28/*28, *6/*6, or double heterozygous for *28 and *6). Patients were randomized (1:1) to receive either low or high dose of IRI given i.v. (90 min) on day 1 in each genotype group. The low and high dose of IRI were 80mg/m2 and 200 mg/m2 in the wild-type group, 80 mg/m2 and 150 mg/m2 in the heterozygous group, 40 mg/m2 and 80 mg/m2 in the homozygous group. S-1 was administered orally at a dose level set on the basis of the body surface area (BSA): 40 (BSA&lt;1.25 m2), 50 (BSA≥1.25 to&lt;1.5 m2 ) or 60 mg (BSA≥1.5 m2) twice a day on day1-7. Courses were repeated every 2 weeks, unless disease progression, unacceptable toxicity or patient refusal. The primary endpoint was to explore the safety and efficacy on different doses of IRI combined with S-1 according to UGT1A1 polymorphism. Based on the frequency of UGT1A1*28 and UGT1A1*6 gene polymorphism in Asian gastrointestinal cancer patients, the chi-square test and fisher exact test were used to evaluate the planned sample size which is 100 in total: 40 for the wild-type, 40 for the heterozygous and 20 for the homozygous group. Until now, 8 patients have been enrolled. Clinical trial information: ChiCTR-OCH-12002472.

UGT1A1 Gene Polymorphisms and the Toxicities of FOLFIRI in Chinese Han Patients with Gastrointestinal Cancer

Neutropenia and diarrhea are the common dose-limiting toxicities of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan related toxicities. This study aims to investigate the association between UGT1A1 gene polymorphisms and irinotecan related toxicities in Chinese Han gastrointestinal cancer patients receiving FOLFIRI regimen chemotherapy. A total of 94 gastrointestinal cancer patients with metastasis (72 colon and rectum, 20 stomach, 1 pancreas and 1 duodenum), were enrolled from 2007 to 2010 in Shanghai Ruijin Hospital. All patients received standard dosage of FOLFIRI regimen (irinotecan 180mg/m2 d1, CF 200mg/m2 d1-d2, 5-FU 400mg/m2 d1-d2, followed by continuous infusion of 5-FU 600mg/m2 for 22h d1-d2, every 2 weeks). UGT1A1 gene polymorphisms (*60 -3279T > G, *93 -3156G > A, *28 -53TA6 > TA7, *6 211G > A) were detected by direct sequencing of DNA extracted from peripheral blood. The incidence of neutropenia, diarrhea, and time to severe toxicity were recorded. The relationship between UGT1A1 gene polymorphisms and toxicities was analyzed. The frequencies of UGT1A1*60 (-3279 G/G), UGT1A1*93 (-3156 A/A), UGT1A1*28 (-53 7/7) and UGT1A1*6 (211 A/A) homozygote were 6.4% (6/94), 1.1% (1/94), 1.1% (1/94) and 2.1% (2/94), respectively. The incidences of grade 3/4 neutropenia and diarrhea were 53.2% (50/94) and 12.8% (12/94), respectively. Comparing those with wild type, patients with UGT1A1*28 or *93 allele had significantly high risk of grade 3/4 diarrhea (6/7, 7/7 vs. 6/6: 27.8% vs. 9.2%, OR=3.791, P=0.034; G/A, A/A vs. G/G: 29.4% vs. 9.1%, OR=4.167, P=0.023). No relationship was found between UGT1A1 allele polymorphism and grade 3/4 neutropenia. The baseline serum total bilirubin was elevated in UGT1A1*28, *93 allele carriers and *60 homozygote, but with no relationship with severe toxicities. In Chinese Han gastrointestinal cancer patients receiving standard FOLFIRI regimen, UGT1A1*28 or *93 allele carriers may have high risk of severe diarrhea.

UGT1A1*28 and *6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

Nilotinib, a second-generation tyrosine kinase inhibitor of BCR-ABL, has shown superior efficacy compared with imatinib for the treatment of chronic myelogenous leukemia (CML). Unconjugated hyperbilirubinemia has been the most frequent adverse event with laboratory abnormality observed in clinical trials of nilotinib. The homozygosity for uridine diphosphate glucuronosyltransferase (UGT) 1A1*28 polymorphism has been reported to increase the risk of nilotinib-induced unconjugated hyperbilirubinemia in Caucasians. However, the frequency of UGT1A1*28 is low in Asians, including Japanese. On the other hand, the UGT1A1*6 allele mutation, which is extremely rare in Caucasians, is more frequent than the UGT1A1*28 allele in the Japanese population. Herein, we present a patient with CML who developed grade 3 unconjugated hyperbilirubinemia after being treated with nilotinib. We found that the patient was heterozygous for both UGT1A1*28 and *6. Our findings suggest that the compound heterozygosity for UGT1A1*28 and *6 could be a cause of unconjugated hyperbilirubinemia during nilotinib treatment.

Frequency of UGT1A1*28 gene polymorphism in Chinese gastrointestinal cancer patients and its relationship with irinotecan-related diarrhea.

451 Background: The incidence of irinotecan-related adverse events was associated with the polymorphism of uridine diphosphate glucuronosyltransferases (UGTs) gene, and demonstrated as obvious ethnic diversity. The aim of this study is to observe the frequency and severity of various adverse events in Han patients with advanced gastrointestinal cancer who was treated with irinotecan-based therapy. Simultaneously, the relationship between the severe adverse events and UGT1A1 gene promoter polymorphism (UGT1A1*28) was investigated. Methods: A total of 109 patients (65 men and 44 women; median 57 years; range: 34-76 years) with advanced gastrointestinal carcinoma receiving irinotecan-based chemotherapy were enrolled. The adverse events during the course chemotherapy, the pretreatment serum bilirubin level, as well as the time to the Grade 3-4 toxicities occurrence were recorded. Genomic DNA was extracted from the peripheral blood to detect the polymorphism of UGT1A1*28 (TATA box thymine-adenine TA repeats). The relationship between the severity of adverse events and UGT1A1*28 polymorphism was investigated. Results: Of all these 109 enrolled patients, 90 patients were identified with thymine-adenine (TA)6/(TA)6 genotype, 19 patients with the thymine-adenine (TA)6/(TA)7 genotype, and no (TA)7/(TA)7 genotype was found. Forty-six and 12 patients developed grade 3-4 neutropenia, while 8 and 5 patients occurred grade 3-4 diarrhea in (TA)6/(TA)6group and (TA)6/(TA)7 group, respectively. The occurrence of grade 3-4 diarrhea but not neutropenia was closely related with (TA)6/(TA)7 genotype in UGT1A1 promoter region in patients receiving irinotecan-based chemotherapy (P=0.033). Conclusions: The frequency of UGT1A1*28 gene polymorphism in Han patients is 17.4%, which is lower than that reported in western populations. The marked increase in grade 3-4 diarrhea is related with (TA)6/(TA)7 genotype of UGT1A1 in patients receiving irinotecan-based chemotherapy. [Table: see text]

Indispensability of UGT1A1*6 genotyping in Japanese cancer patients treated with irinotecan

We would like to congratulate Onoue and colleagues [1] for their excellent article on investigation of the relationship between severe neutropenia and UGT1A1 and SLCO1B1 polymorphisms. In the article, they suggested that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients. The significance was observed in not only UGT1A1*6 ?/? patients but also UGT1A1*6 ?/cases. Odds ratios were surprisingly high; 5.19 in UGT1A1*6 ?/cases and 7.63 in UGT1A1*6 ?/? cases. A metaanalysis of nine Euro-American studies revealed that frequency of grades III and IV hematologic toxicities increased in the patients with UGT1A1*28 ?/? genotype at a high doses of irinotecan [2]. At lower doses (B150 mg/m), the risk of hematologic toxicity in patients with UGT1A1*28 ?/? genotype was not statistically significantly different from that among patients with UGT1A1*28 ?/or UGT1A1*28 -/genotype [2]. Taking account of the results, it seems appropriate that genotyping of UGT1A1*28 could be omitted for the patients treated at a low dose of irinotecan in western countries. On the other hand, the significant contribution of UGT1A1*6 ?/to grades III and IV neutropenia and diarrhea was also clearly observed in Japanese prospective multi-institutional analysis for gynecologic patients treated with a low dose of irinotecan (60 mg/m, 3 weeks on and 1 week off) and cisplatin [3]. The UGT1A1*6 ?/genotype was identified as an independent risk factor for grades III and IV neutropenia (hazard ratio = 6.54), and grades III and IV diarrhea (hazard ratio = 7.45). We are so surprised to see almost the same odds ratio for severe neutropenia in heterogeneously treated cohort with irinotecan [1] as in our homogeneously treated cases [3]. It is noteworthy that severe toxicities in UGT1A1*6 ?/cases were observed in two separate studies, even at a low dose of irinotecan. Recently in Japan, genotyping of UGT1A1*28 and *6 has been approved by the Japanese Organization of the Ministry of Health, Labor and Welfare; however, there exists an argument against routine use of UGT1A1 genotype testing for the patients who will be treated with irinotecan. It is true that UGT1A1 genotyping is not a magic tool to certify no toxicities caused by irinotecan, as there are some cases that experience severe toxicities in UGT1A1 wild-type cases. We would emphasize that one half of the cases who experienced grade III–IV neutropenia were treated at a lower dose of irinotecan and increasing doses of irinotecan were not related with increase toxicities in the analysis by Onoue and colleagues [1]. On the contrary, a report on a Japanese population suggested the metabolic ratios were variable according to administrated dose of irinotecan in patients with homozygosity of UGT1A1*6 or heterozygosity of UGT1A1*6 [4]. Thus, dose matters of irinotecan have been unresolved in Japanese patients with different frequency of UGT1A1*28 and *6 from western patients. Together, the utility of M. Takano (&) M. Kato T. Yoshikawa T. Goto K. Furuya Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan e-mail: mastkn@ndmc.ac.jp

A phase I/II study of combination therapy of S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

e15023 Background: To investigate S-1 and irinotecan (CPT-11) combination as an alternative to infusional 5- fluorouracil/leucovorin plus CPT-11, we performed a phase I/II trial to determine maximum tolerated dose (MTD), efficacy and toxicity in metastatic or recurrent colorectal cancer. In addition, we evaluated the association between genotypes of candidate genes and phenotypes. Methods: S-1 was administered orally at a dose of 70 mg/m2 (level I-III) or 80 (IV and V) from day 1 to 14. CPT-11 was given i.v. on day 1, stepping up to 175 (level I), 200 (II), 225 (III and IV) or 250 (V) mg/m2 . The treatment was repeated every 3 weeks. The association of the UGT1A1 genotypes (*6, *28, and *60) and CYP2A6 genotypes (*4, *7, and *9) with toxicities or efficacy were analyzed in patients who participated in phase II portion. Results: Twenty-three patients entered the phase I and 30 enrolled in phase II study. The MTD of S-1 and CPT-11 was considered to be 80 mg/m2 and 250 mg/m2, respectively. The dose-limiting toxicities (DLTs) were diarrhea and neutropenia. The recommended dose (RD) was determined at a S-1 dose of 80 mg/m2 and a CPT- 11 dose of 225 mg/m2. The overall response rate was 66.7% (95% CI, 48.7–84.6) at the RD level. Median time to progression was 7.6 months (95 % CI, 5.7–9.5). Median survival time was not reached. Grade3–4 neutropenia was observed in 53.4% of the patients. Grade 3–4 nonhematologic toxicities were diarrhea (16.7%) and asthenia (6.7%). The frequencies of UGT1A1*60, *28, and *6 allele were 25.8%, 10.3%, and 15.5%, respectively. Homozygous for *28 or *6 were not observed. All three double heterozygous for *28 and *6 experienced grade 3–4 neutropenia. The allele frequencies of CYP2A6*4, *7, and *9 were 15.5%, 8.6%, and 29.3%, respectively. There were no association between CYP2A6 genotypes and response rates or toxicities. Conclusions: The combination of S-1 and CPT-11 was effective and had manageable toxicities in patients with metastatic or recurrent colorectal cancer. [Table: see text] No significant financial relationships to disclose.

Increased Frequency of Uridine Diphosphate Glucuronosyltransferase 1A1 7/7 in Patients Experiencing Severe Irinotecan-Induced Toxicities

Uridine diphosphate glucuronosyltransferase (UGT) 1A1 7/7 polymorphism has been linked with an increased risk of irinotecan-induced severe toxicities. We evaluated UGT1A1 polymorphism in patients developing grade 3/4 toxicity after initiation of irinotecan to determine the frequency of this polymorphism in this population. Twenty patients with grade 3/4 irinotecan-induced toxicity underwent UGT1A1 genotyping in an exploratory study. The frequency of UGT1A1 7/7 and the pattern of toxicity associated with this polymorphism were described. Forty percent of patients with grade 3/4 toxicities had a UGT1A 7/7 polymorphism (vs. 10% in general population). Six of 7 patients requiring hospitalization, 7 of 10 patients with grade 4 neutropenia, and 3 of 3 patients with grade 4 diarrhea, had UGT1A1 7/7 polymorphism. Uridine diphosphate glucuronosyltransferase 1A1 7/7 is prevalent in patients with irinotecan grade 3/4 toxicity, especially in patients with treatment-related hospitalizations and grade 4 toxicities. Our data support the need for more prospective studies that evaluate the predictive value of UGT1A1 as well as UGT1A1-based dosing in patients receiving irinotecan.

Evaluation of Effects of Polymorphism for Metabolic Enzymes on Pharmacokinetics of Carvedilol by Population Pharmacokinetic Analysis

In our previous study it was observed that the frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in patients who have a low level ability of glucuronidation were significantly higher than those in patients with a high level of ability of glucuronidation. The same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. The purpose of this study was to evaluate the effects of the polymorphism on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Population pharmacokinetic analysis was performed using 373 plasma concentrations from 41 patients with chronic heart failure or angina pectoris. A one compartment pharmacokinetic model with first-order absorption (for oral dosing) was used to describe the concentration-versus-time data for carvedilol. We examined the effects of various clinical and genetic covariables in the regression models for clearance and volume of distribution. The results suggested that the factors of interindividual variation for carvedilol clearance were creatinine clearance and polymorphisms of UGT2B7 and CYP2D6 in the Japanese population with heart disease. It was estimated that UGT2B7*3 decreased the clearance of carvedilol by 37%, but UGT2B7*2 did not show any effect. Clearance in the patients who have intermediate activity of CYP2D6 was decreased by 39%.

UGT1A1(TA)n promoter polymorphism—A new case of a (TA)8 allele in Caucasians

Gilbert's syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The causative mutation in Caucasians is almost exclusively a TA dinucleotide insertion in the TATA box of the UGT1A1 promoter. Affected individuals are homozygous for the variant promoter and have 7 instead of 6 TA repeats. The aim of the present study was to determine the genotypes of UGT1A1(TA)n promoter polymorphism in the healthy Slovenian population and to investigate the association of genotypes with serum bilirubin levels. 236 healthy subjects were genotyped by single-strand conformation polymorphism analysis, which was validated by sequence analysis. The frequencies of genotypes were as follows: (TA)6/6 (38.1%), (TA)6/7 (47.9%), (TA)7/7 (13.6%). There was a statistically significant association of genotypes with serum bilirubin levels (p<0.001). Subjects with genotype (TA)7/7 had the highest and subjects with genotype (TA)6/6 the lowest total serum bilirubin levels. One individual in the group had the rare genotype (TA)7/8 (0.4%). Analysis of his family showed the following genotypes: (TA)6/8 in his father and sister and (TA)7/8 in his two brothers. In conclusion, the frequency of UGT1A1(TA)n promoter polymorphism genotypes was determined for the first time in the Slovenian population and is similar to frequencies observed in other Caucasian populations. The extremely rare (TA)8 allele in Caucasians was found also in Slovenians.

Use of Fully Denaturing HPLC for UGT1A1 Genotyping in Gilbert Syndrome

Gilbert syndrome is an inborn error of bilirubin conjugation caused by mutations in the conjugating enzyme uridine diphosphate glucuronyltransferase (UGT1A1) (1). UGT1A1 activity is moderately reduced in Gilbert syndrome, causing low-grade nonhemolytic unconjugated hyperbilirubinemia without other biochemical or clinical features of hepatic or hematologic pathology. Bilirubin concentrations typically fluctuate over time and tend to be increased in response to metabolic stress such as intercurrent illness and fasting(2). The clinical importance of Gilbert syndrome derives from its high population prevalence. The causative mutation in Caucasians is almost exclusively a dinucleotide insertion in the TATA box of the UGT1A1 promoter. The most common UGT1A1 promoter contains the sequence (TA)6TAA; insertion of an extra TA reduces expression of the UGT1A1 gene to 20%–30% of reference values (3). The frequency of the (TA)7TAA allele (also known as UGT1A1*28 ) in the Caucasian population is ∼0.35; therefore, nearly all Caucasians with Gilbert syndrome are homozygous for this allele(4). UGT1A1*28 is less frequent in Asians. A significant proportion of Asians with Gilbert syndrome have UGT1A1*28 as one mutant allele, but other substitutions that diminish UGT1A1 activity are more common, including p.G71R and p.P229Q(5). Indeed, given the frequency of UGT1A1*28 , 10%–15% of Caucasians are homozygous for this allele; however, the prevalence of clinical Gilbert syndrome has been estimated at 5%. The difference between these 2 values may reflect an ascertainment bias, relatively low penetrance of UGT1A1*28 homozygosity, or a combination of both(1)(3) A variety of assays adaptable for clinical use can detect the UGT1A1*28 allele, such as polyacrylamide gel electrophoresis (PAGE), direct sequencing, fluorescence resonance energy transfer with melting curve analysis, pyrosequencing, and denaturing HPLC [(dHPLC); reviewed in Ref. (6)]. We used dHPLC to separate fragments based on size rather than heteroduplex melting characteristics as …