Program

PO4-10-11

Correlation Between Cytidine Deaminase Polymorphism and Gemcitabine in Efficacy and Toxicity

[Speaker] Suda Vannaprasaht:1
[Co-author] Duanggamon Muengsaen:1, Kosin Wirasorn:2, Kritiya Butthongkomvong:3, Luangyot Thongthieang:4, Parichart Pongthai:4, Wichittra Tassaneeyakul:1
1:Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand, 2:Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand, 3:Chemotherapy Unit, Udonthani Cancer Hospital, Udonthani, Thailand, 4:Medical Oncology Unit, Internal Medicine Department, Khon Kaen Hospital, Khon Kaen, Thailand

Introduction
Gemcitabine is recommended for various solid tumors and metastasis cancer. dFdC is converted to an inactive form 2', 2'-difluorodeoxyuridine by cytidine deaminase (CDA). Polymorphism of CDA genes such as CDA*2 and CDA+435C>T affected CDA activity leading to altered levels of dFdC active form. Patients who carried CDA*1/*1 genotype have a lower the mean of CDA activity than CDA*1/*2 and CDA*2/*2 genotypes. Moreover, people who carried CDA+453T/T genotype showed increasing CDA gene expression in peripheral blood mononuclear cell which causes on o increase of CDA activity in this group. Therefore, lowering of CDA activity in wild type group lead to higher efficacy but a higher risk of toxicity of gemcitabine than mutant allele groups. Therefore, the aim of this study was to investigate correlation between CDA polymorphisms and gemcitabine response rate and adverse effects.
Method
One hundred twenty-nine cancer patients treated with gemcitabine-base chemotherapy were enrolled in this study from Srinagarind Hospital, Khon Kaen Hospital and Udonthani Cancer Hospital. DNA was extracted from buffy coat and analyzed for CDA*2, CDA+435C>T genotype by using real-time polymerase chain reaction with TaqMan® probe. Retrospective clinical data of each cancer patient was reviewed.
Results
The prevalence of CDA*1/*1 and CDA*1/*2 in cancer patients was 86.05% and 13.95%, respectively. CDA*2/*2 was not found in this study. Frequencies of CDA+435C/C, C/T and T/T in cancer patients were 70.54%, 26.36%, 3.1%, respectively. Patients with CDA+435C/C genotypes had significantly lower incidence of progressive disease than CDA+435C/T and CDA+435T/T genotypes (34.18% vs 55.17%, respectively) (P = 0.005). However, this study did not show a correlation between CDA*2 polymorphisms and gemcitabine response rate. CDA*1/*1 genotype patients had significant higher incidence of anemia than CDA*1/*2 genotype (33.3% VS 5.6 %, respectively) (P = 0.006). Similarly, patients who carried CDA+435C/C genotype had higher incidence of anemia than mutant allele groups (39.6% VS 21.11%, respectively) (P = 0.043).
Conclusion
CDA genotype significantly influenced gemcitabine efficacy and toxicity. Therefore, CDA genotyping should be investigated in patients treated with gemcitabine to predict clinical outcome and adverse effects.

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