Dihydropyrimidine Dehydrogenase Gene Variation and Its Association with 5-Fluorouracil Toxicity in Colorectal Patients

Ebrahim Salehifar; Mohammad Javad Abd Haghighi; Reza Negarandeh; Ghasem Janbabai; Fatemeh Safgafi; Hossein Jalali

doi:10.31557/apjcb.2018.3.3.65

Authors

Ebrahim Salehifar 1 Professor of Clinical Pharmacy, Pharmaceutical Research Center, Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Mohammad Javad Abd Haghighi Pharm D Candidate, Student Research Committee, Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
Reza Negarandeh Pharm D Candidate, Student Research Committee, Gastrointestinal Cancer Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
Ghasem Janbabai Associate Professor of Hematology-Oncology, Gastrointestinal Cancer Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Fatemeh Safgafi Assistant Professor of Clinical Pharmacy, Department of Clinical Pharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Assistant Professor of Clinical Pharmacy, Department of Clinical Pharmacy, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Hossein Jalali PhD by Research candidate, Thalassemia Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

DOI:

https://doi.org/10.31557/apjcb.2018.3.3.65

Keywords:

Colorectal cancer- DPYD- IVS14 1G>A- Polymorphism

Abstract

Objective: Dihydropyrimidine dehydrogenase (DPD), an enzyme translated by DPD gene (DPYD), has a critical role in the metabolism of 5-fluorouracil (5FU). In this study we aimed to investigate the frequency of the IVS14+1 G>A, 2194G>A, 2846 A>T mutations in the DPYD gene in colorectal cancer patients in north of Iran and their association with side effects of 5FU.
Methods: Venous blood samples of 89 colorectal cancer patients were drawn. After the DNA extraction from nuclear cells, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the frequency of the IVS14+1 G>A and 2846 A>T mutations. Tetra-Primer ARMS PCR optimization method was used to detect the 2194 G>A mutation. Side effects were classified according to CTCAE (common terminology criteria for adverse events V. 4) and the association between different polymorphisms and side effects were evaluated.
Results: Of 89 colorectal patients, the frequency of IVS14+1 G>A and 2846 A>T polymorphism was 4 (5.1%) and 1 (1.1%), respectively. The 2194 G>A polymorphism was not detected. All 4 patients were heterozygous for IVS14+1 G>A mutation, whereas the only patient with 2846 A>T polymorphism was homozygous. Some adverse effects of 5FU including diarrhea, vomiting, mucositis and stomatitis were more frequent in patients with IVS14+1 G>A polymorphism.
Conclusion: The prevalence of IVS14+1 G>A mutation in our patients were relatively high and was associated with a higher occurrence of 5FU-associated toxicities.