D'ALESSANDRO, Natale

LABBOZZETTA, Manuela

NOTARBARTOLO DI VILLAROSA, Monica

POMA, Paola

VIVONA, Nicoletta

Archivio istituzionale della ricerca - Università di Palermo

  Analysis of UGT1A1*28 and DPYD*2A polymorphisms in Sicilians patients with metastatic colorectalcancer treated with Irinotecan and 5-fluorouracil.M. Labbozzetta1, N. Vivona1, P. Poma1, M. Notarbartolo1, N. D'Alessandro11Dept. of Sciences for Health Promotion and Mother and Child Care 'Giuseppe D'Alessandro' (Farmacologia), University of Palermo,Italy.Irinotecan (CPT-11), in combination with 5-fluorouracil (5-FU) and leucovorin, is used in the treatment of metastaticcolorectal cancer (mCRC). Its active metabolite SN-38 is extensively metabolized to the inactive glucuronide by severalUDP-glucuronosyltransferase (UGT), which include UGT1A1, UGT1A6, UGT1A9 and UGT1A7. The main dose-limitingtoxicities of CPT-11 are delayed diarrhea and neutropenia and polymorphisms of the UGT1A family members maydeterminate variability in the toxic response to the drug among the patients. The most common genetic variant described todate in the UGT1A1 gene is a dinucleotide repeat polymorphism in the TATA box region of the UGT1A1 promoter. Thevariant allele consists of seven TA repeats in the A(TA)nTAA motif (UGT1A1*28), whereas six TA repeats characterizethe common allele (UGT1A1*1). The presence of UGT1A1*28 was previously found to decrease UGT1A1 geneexpression and to be associated with CPT-11-related toxicity.Dihydropyrimidine dehydrogenase (DPYD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. Anuncommon variant (allelic frequency of 0,7%) of the DPYD gene, consisting of a G to A mutation in the splicingrecognition sequence of intron 14 (IVS14+1G>A) of the DYPD encoding gene (DPYD*2A), produces a non-functionalenzyme due to skipping of exon 14 and in homozygosis is associated with a life-threatening toxicity of 5-FU.The aim of our study was to examine both the allelic frequency and the influence on toxicity of UGT1A1*28 andDPYD*2A polymorphisms in 50 Sicilian patients with mCRC treated with CPT-11 and 5-FU. There are not data about theallelic frequency of these variants for Sicilian people.The TA repeat promoter polymorphism UGT1A1*28 was detected by PCR and automatic sequencing. The mutation in theDPYD gene introduces a restriction site and was detected by PCR-RFLP. Our results showed that 28% of the patientsexhibited the UGT1A1*28 polymorphism. Genotypes frequencies for UGT1A1*1/*1, UGT1A1*1/*28 andUGT1A1*28/*28 were 72% (36 patients), 16% (8 patients) and 12% (6 patients), respectively. The allelic frequencies ofUGT1A1*1 and UGT1A1*28 were 80% and 20%, respectively. The frequency of the UGT1A1*28 was lower than that ofother Caucasian populations (38.7%). This result might depend on the limited number of patients studied till now orrepresent an own characteristic of a population made up mainly of Sicilians.We examined the relationship between the genotypes and the toxicity of CPT-11 in the patients. Homozygous andheterozygous patients for the UGT1A1*28 polymorphism showed a higher incidence of neutropenia (22%) compared towild type patients (4%). A statistically significant (P = 0.026) higher incidence of diarrhea (grade 2-3) was observed inpatients carrying a UGT1A1*28 allele (55%) compared to UGT1A1*1/*1 patients (16%).Accordingly to the rarity of the DPYD*2A mutation, this polymorphism was not found in any of our patients. Clearly,these data exclude the occurrence in any patient of a 'Combined pharmacogenetic syndrome', consisting of a heterozygosityfor both DPYD*2A and UGTA1*28, which could cause very severe toxicity.The present results confirm that screening for the UGT1A1*28 allele may be effective in identifying patients at risk ofCPT-11 toxicity. Possibly, however, other variant alleles of UGT1A (UGT1A6*2, UGT1A7*3 and UGT1A9*22) might betaken into consideration to prevent severe adverse event following CPT-11 administration.Powered by TCPDF (www.tcpdf.org)                               1 / 1

Analysis of UGT1A1*28 and DPYD*2A polymorphisms in Sicilians patients with metastatic colorectal cancer treated with Irinotecan and 5-fluorouracil.

https://iris.unipa.it/retrieve/handle/10447/87743/97832/197.pdf

Analysis of UGT1A128 and DPYD2A polymorphisms in Sicilians patients with metastatic colorectal cancer treated with Irinotecan and 5-fluorouracil.

Abstract

Similar works

Full text

Available Versions

Archivio istituzionale della ricerca - Università di Palermo