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Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Authors
 김효송 ; 라선영 ; 박형순 ; 신상준 ; 안중배 ; 이지현 ; 임선민 ; 권우선 ; 김혜련 
Citation
 Cancer Chemotherapy and Pharmacology, Vol.72(4) : 825~835, 2013 
Journal Title
 Cancer Chemotherapy and Pharmacology 
ISSN
 0344-5704 
Issue Date
2013
Abstract
PURPOSE: The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients. METHODS: A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ (2) test. RESULTS: Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type. CONCLUSION: Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/88016
DOI
10.1007/s00280-013-2258-y
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Pharmacology
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
1. 연구논문 > 5. Research Institutes > 생체방어연구센터
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
Yonsei Authors
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Link
 http://link.springer.com/article/10.1007%2Fs00280-013-2258-y
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