Severe CPT-11 toxicity in patients with Gilbert's syndrome: Two case reports

Wasserman, Ernesto; Myara, Anne; Lokiec, François; Goldwasser, François; Trivin, F; Mahjoubi, M.; Misset, J.L.; Cvitkovic, Esteban

doi:10.1023/a:1008261821434

Cited by 190 publications

(94 citation statements)

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“…14,15 A significant correlation between SN-38 and bilirubin glucuronidation has been found, high serum T-Bil concentration seemed to be a reasonably good predictor of lower irinotecan clean rate. [16][17][18] In the present study, the (TA)7 allele was significantly associated with higher T-Bil concentrations, in line with previous reports. 15,19 However, different to Koreans, no association between 211A allele and bilirubin level was found.…”

Section: Intra-ethnic Differences In Genetic Variantssupporting

confidence: 93%

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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Variants within the human UGT1A1 gene are associated with irinotecan induced severely adverse reactions and hyperbilirubinemia. Intra-ethnic differences in the genetic variation and haplotypes of UGT1A1 gene have been analyzed in the present study. Relationship between the concentrations of total serum bilirubin (T-bil) and haplotype structure of UGT1A1 in healthy people were also evaluated. We genotyped five functional polymorphisms including À3279T4G and À3156G4A in the enhancer region, (TA)647 in the TATA box, and 211G4A (G71R), 686C4A (P229Q) in the exon1 region of UGT1A1 in three groups of healthy Chinese ethnic populations, consisting of 264 subjects of She origin, 539 of Han origin and 273 of Dong origin. The distribution of À3279T4G, (TA)647, 211G4A of UGT1A1 differed greatly as between the three ethnic groups. All of six haplotypes differed considerably between at least two of the three groups, which highlighted the need to analyze clinically irinotecan toxicity relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population. Total bilirubin concentration in homozygous carriers of the À3279G and (TA)7 allele were significantly higher than those in heterozygous carriers or homozygous carriers of wild-type alleles. Carriers of the variant haplotypes (À3279G; À3156A; (TA)7; 211G; 686C) had higher serum T-Bil concentrations compared with the other groups. Our results indicate that heterogeneity among different ethnic populations is possibly the result of microevolution and is relevant to studies into the effect of tailored drug treatment.

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Section: Intra-ethnic Differences In Genetic Variantssupporting

confidence: 93%

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

et al. 2006

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“…[119][120][121] Polymorphisms of the UGT1A1 Gene as Risk Factors for Drug-Induced Toxicity Patients affected by Gilbert's syndrome display lower glucuronidation rates for a number of therapeutic drugs including acetaminophen, tolbutamide and lorazepam. [20][21][22][34][35][36][37] Since Gilbert's syndrome is associated with the UGT1A1*28 (TA 7 polymorphism), it is more likely that patients with this allele will present an altered drug clearance compared to patients with the wild-type genotype. However, a correlation between the presence of variant UGT1A1 alleles and altered rates of glucuronidation has not been systematically demonstrated.…”

Section: Ugt1a1mentioning

confidence: 99%

“…SN-38 undergoes significant glucuronidation to form the corresponding inactive glucuronide (10-O-glucuronyl-SN-38 (SN-38-G)) 124 and UGT1A1 isoenzyme was suggested to be the predominant human UGT involved in the formation of SN-38-G. 35 Individuals with Gilbert's syndrome are at greater risk to experience irinotecaninduced toxicity. 37 Therefore, inherited differences in irinotecan glucuronidating capacity, such as those caused by UGT1A1 promoter polymorphisms, may have an important influence on the pharmacokinetics, the pharmacologic effects and toxicity of this drug. This hypothesis is supported by the observation of an inverse relation between SN-38 glucuronidation and the severity of diarrheas occurring in patients treated with irinotecan.…”

Section: Ugt1a1mentioning

confidence: 99%

“…Recent work has demonstrated that genetic variations affect glucuronidation rates and influence the risk of an individual to develop drug-induced toxicity. 35,37,[61][62][63][64] The role of genetic factors in determining variable rates of glucuronidation of hormones, tobacco smoke carcinogens, environmental pollutants and dietary components is poorly understood. Recent findings suggest that metabolic alterations may actually determine the degree of exposure of an individual to toxic or carcinogenic substances over a long time period and may contribute to modify one's susceptibility to diseases such as cancer.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

2003

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UDP-glucuronosyltransferase (UGT) enzymes comprise a superfamily of key proteins that catalyze the glucuronidation reaction on a wide range of structurally diverse endogenous and exogenous chemicals. Glucuronidation is one of the major phase II drug-metabolizing reactions that contributes to drug biotransformation. This biochemical process is also involved in the protection against environmental toxicants, carcinogens, dietary toxins and participates in the homeostasis of numerous endogenous molecules, including bilirubin, steroid hormones and biliary acids. Over the years, significant progress was made in the field of glucuronidation, especially with regard to the identification of human UGTs, study of their tissue distribution and substrate specificities. More recently, the degree of allelic diversity has also been revealed for several human UGT genes. Some polymorphic UGTs have demonstrated a significant pharmacological impact in addition to being relevant to drug-induced adverse reactions and cancer susceptibility. This review focuses on human UGTs, the description of the nature of polymorphic variations and their functional impact. The pharmacogenomic implication of polymorphic UGTs is presented, more specifically the role of UGT polymorphisms in modifying cancer risk and their impact on individual risk to drug-induced toxicities.

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“…An interesting case-report on two patients with metastatic colorectal cancer and Gilbert's syndrome (a chronic nonhaemolytic unconjugated hyperbilirrubinaemia caused by a reduction in the activity of UGT1A1) treated with CPT-11 provided the first clinical evidence linking deficiency in the UGT1A1 activity and irinotecan-related toxicity (Wasserman et al, 1997).…”

mentioning

confidence: 99%

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

et al. 2004

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SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/ 45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P ¼ 0.005). These results maintained the statistical significance in logistic regression analysis (P ¼ 0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1*28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1*28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1*28 polymorphism showed a trend to a poorer OS (P ¼ 0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1*28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.

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Severe CPT-11 toxicity in patients with Gilbert's syndrome: Two case reports

Cited by 190 publications

References 6 publications

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

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