Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan‐based chemotherapy

Abstract

BACKGROUNDIn the current Phase II study, the authors evaluated the association between genomic polymorphic variants in uridine diphosphate glucuronosyl transferase (UGT1A1), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TS) genes, and the incidence of the adverse effects of irinotecan and raltitrexed in previously heavily treated patients with metastatic colorectal carcinoma.METHODSFifty‐six patients received irinotecan (at a dose of 80 mg/m2 on Days 1, 8, 15, and 22 every 5 wks), combined with raltitrexed (at a dose of 3 mg/m2 every 3 wks). Genotyping for the MTHFR C677T polymorphism, the TATA box region in the UGT1A1 promoter, and tandem repeats in the TS promoter was performed on genomic DNA extracted from blood. Nineteen variables related to patient, disease, and treatment characteristics, together with genotypes, were analyzed using a binary logistic regression model with stepwise selection to evaluate their correlation with adverse reactions.RESULTSToxicities (determined according to the National Cancer Institute Common Toxicity Criteria) were evaluated in 169 cycles. Grade 3/4 neutropenia was reported to occur in 2% of cycles, Grade 2–4 nausea was reported to occur in 19% of cycles, Grade 2–4 emesis was reported to occur in 9% of cycles, Grade 2–4 diarrhea was reported to occur in 20% of cycles, Grade 2/3 fatigue was reported to occur in 11% of cycles, and Grade 3/4 hepatic toxicity was reported to occur in 7% of cycles. Homozygosis for six TA repeats in the promoter region of the UGT1A1 gene was found to be the main predictive factor for diarrhea (P < 0.00005), emesis (P = 0.0001), and fatigue (P = 0.007). Homozygosis for two tandem repeats in the TS promoter was found to be predictive of a reduced incidence of fatigue (P = 0.044). MTHFR C677T polymorphism was not found to be associated with any adverse reaction.CONCLUSIONSIn the current study, UGT1A1 promoter polymorphism was found to be predictive of the risk of diarrhea, emesis, and fatigue caused by chemotherapy with irinotecan and raltitrexed. Screening for UGT1A1 promoter polymorphism may be clinically useful for identifying patients at a higher risk of developing a severe or potentially life‐threatening toxicity after irinotecan‐based chemotherapy. Cancer 2006. © 2006 American Cancer Society.

Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

“…Patients were predominantly Caucasians in 11 trials. Four trials did not clearly report the race of the participants (16,20,22,23). The patients in these four trials, however, might have been Caucasians because these trials were conducted in Europe or America and the reported frequency of the UGT1A1*28 allele was similar to that of Caucasians.…”

“…If the patients in a trial received different irinotecan doses and only combined toxicity-related data (or REG data) were available, we calculated the average dose. In one study (16), the numbers of chemotherapy cycles with neutropenia in each genotype group were provided instead of the number of patients. We calculated the number of patients as C × tN/tC, where C is the number of chemotherapy cycles with neutropenia in each genotype group, tC is the total number of chemotherapy cycles with neutropenia, and tN is the total number of patients with neutropenia.…”

“…UGT1A1*28 has been shown to be associated with decreased SN-38 glucuronidation in humans (3)(4)(5)(6)(7)(8)(9)(10)(11). The association between the UGT1A1*28 genotype and irinotecan-induced neutropenia has been extensively studied (3)(4)(5)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Seven of these studies found that UGT1A1*28/*28 patients had an elevated risk of neutropenia compared with those carrying UGT1A1*1 allele(s) (refs.…”

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

“…Hepatic expression of UGT shows little interindividual variation, as opposed to the high interindividual variability found in the gastrointestinal tract (Strassburg et al, 1998(Strassburg et al, , 2000, further accentuated by the differential enzyme expression within different segments of the gastrointestinal tract (Strassburg et al, 1998(Strassburg et al, , 2000Antonio et al, 2003;Basu et al, 2004). Genetic polymorphisms have been described for several UGT, and some of them have been associated with interindividual variations in drug effect (Chung et al, 2005) and toxicity (Marsh and McLeod, 2004;Massacesi et al, 2006). Therefore, the identification of specific enzymes involved in the metabolism of a drug is important.…”

Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer

“…Polymerase chain reactions (PCR) were conducted in a total volume of 50 μL containing 100 ng of genomic DNA, 25 pmoles of the UGT1A1 primer (UGT1A1 forward: 5′-GAT TTG AGT ATG AAA TTC CAG CCA G-3′ and UGT1A1 reverse: 5′-CCA GTG GCT GCC ATC CAC T-3′) [21] and the following reagents (obtained from Promega, Madison, WI): 0.1 mM each of dCTP, dGTP, dATP and dTTP; 2.5 mM of MgCl 2 ; 50 mM of potassium chloride; 10 mM of Tris (pH 9.0); 0.1 % Triton-X; and 2.5 U of Taq polymerase. After 35 cycles of amplification (denaturation at 94°C for 30 sec, annealing at 60°C for 1 min, and extension at 72°C for 1 min), the amplification products were electrophoresed in 3% agarose gel and visualized after staining with ethidium bromide.…”