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

Authors
 Hye Ryun Kim  ;  Hyung Soon Park  ;  Woo Sun Kwon  ;  Ji Hyun Lee  ;  Yusuke Tanigawara  ;  Sun Min Lim  ;  Hyo Song Kim  ;  Sang Jun Shin  ;  Jung Bae Ahn  ;  Sun Young Rha 
Citation
 CANCER CHEMOTHERAPY AND PHARMACOLOGY, Vol.72(4) : 825-835, 2013 
Journal Title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN
 0344-5704 
Issue Date
2013
MeSH
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters/genetics* ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/adverse effects* ; Antineoplastic Agents/therapeutic use ; Asian Continental Ancestry Group/genetics ; Carcinoma, Renal Cell/drug therapy* ; Carcinoma, Renal Cell/pathology ; Female ; Genotype ; Humans ; Indoles/adverse effects* ; Indoles/therapeutic use ; Kidney Neoplasms/drug therapy* ; Kidney Neoplasms/pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Proteins/genetics* ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Prospective Studies ; Pyrroles/adverse effects* ; Pyrroles/therapeutic use ; Republic of Korea
Keywords
Renal cell carcinoma ; Sunitinib ; Toxicity ; Polymorphism
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.
Full Text
http://link.springer.com/article/10.1007%2Fs00280-013-2258-y
DOI
10.1007/s00280-013-2258-y
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kwon, Woo Sun(권우선) ORCID logo https://orcid.org/0000-0003-0268-5624
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Kim, Hyo Song(김효송) ORCID logo https://orcid.org/0000-0002-0625-9828
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Park, Hyung Soon(박형순)
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
Lee, Ji Hyun(이지현)
Lim, Sun Min(임선민)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88016
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