Dissertação

Polimorfismo do Gene UGT1A1 associado à toxicidade em pacientes oncológicos tratados com irinotecano (CPT-11) em Belém/PA

Introduction: Studies and reviews the international scientific literature have gathered data to support the role of pharmacogenomics in clinical medicine, specifically genotype UGT1A1*28 and UGT1A1*6 as predictors of toxicity associated with therapy with CPT-11 (irinotecan), because an insert thymin...

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Autor principal: CARRERA, Jackeline de Sousa
Grau: Dissertação
Idioma: por
Publicado em: Universidade Federal do Pará 2017
Assuntos:
Acesso em linha: http://repositorio.ufpa.br/jspui/handle/2011/7248
Resumo:
Introduction: Studies and reviews the international scientific literature have gathered data to support the role of pharmacogenomics in clinical medicine, specifically genotype UGT1A1*28 and UGT1A1*6 as predictors of toxicity associated with therapy with CPT-11 (irinotecan), because an insert thymine-adenine in the promoter region of the UGT1A1 gene TATAbox or a single nucleotide polymorphism in exon 1 of the same gene, causing lesser extent UGT1A1 enzyme and hence lower glucuronidation of the drug. Objective: To investigate the occurrence of polymorphisms in the promoter region of the UGT1A1 gene and associate their presence with the toxicities of manifestation to CPT-11 drug in cancer patients treated at two public hospitals specialized in oncology in Belém /PA. Method: Patients in cancer treatment to CPT-11 base were accompanied by pharmacotherapeutic monitoring method as the occurrence of toxicities. Adverse reactions were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0. The study also analyzed the genetic material of patients, the frequency and distribution of the polymorphism in the UGT1A1 gene by polymerase chain reaction and sequencing. As they could also be evaluated clinical and epidemiological data of the subjects. Results: A total of 31 patients were recruited, the majority (80.6%) treated with modified IFL regimen (120 mg /m² CPT-11), the most frequent gender was female (54.8%) and the primary site of the tumor , predominantly, it was the rectum (41.9%). Among the 27 patients could be genotyped none showed polymorphism in exon 1 (UGT1A1 * 6), but the following alleles were detected as the TATA promoter polymorphism in the gene, TA5/6 (3.7%), TA6/6 (44 , 4%), TA6/7 (37%) and TA7/7 (14.8%). A total of 71 toxicities were observed in 25 patients. The study population is in Hardy-Weinberg equilibrium (P = 0.135). Our study found no significant relationship between the different toxicities manifested in patients with different numbers of variant alleles, but it was observed that patients who had two alleles or a single variant allele had more medical interventions (dose reduction, delay or discontinuation of treatment) due to toxicity than patients in the wild-type allele (p = 0.016). Conclusion: The findings of this study showed a high frequency of adverse reactions to CPT-11 use in the studied patients, even low-dose protocols in relation to other studies, although they have not shown significant differences suggest the continuity of the same order to get larger sample size, considering that when the population was stratified by frequency of medical interventions motivated by toxicity, the carrier of the mutation group, heterozygous or homozygous, had higher intervention rate during treatment. Those patients can present toxicities more severe than compromise the continuity of care.