Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer

Department of Respiratory Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama, Japan.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 09/2010; 66(4):691-8. DOI: 10.1007/s00280-009-1211-6
Source: PubMed


ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the c.421C > A ABCG2 gene polymorphism was associated with gefitinib-induced diarrhea in Caucasian patients with non-small-cell lung cancer. Since c.421C > A ABCG2, resulting in p.Q141K substitution, is more prevalent in Asian populations, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in Japanese patients. c.376C > T, resulting in truncated, non-functional ABCG2, was also investigated.
ABCG2 gene polymorphisms were evaluated in 75 patients with non-small-cell lung cancer treated with gefitinib 250 mg/day orally, and results were correlated with treatment-related adverse effects.
Forty (53.3%) patients harbored c.421A ABCG2 on at least one allele, while the remaining 35 (46.7%) were wild type for c.421C > A. No significant group difference was observed in frequency of gefitinib-related diarrhea or other adverse effects. In addition, the only one patient homozygous for the c.421A allele in this study was not affected with gefitinib-induced diarrhea or interstitial lung disease. Two patients (2.7%) were found to harbor the c.376T allele heterozygously. One of the two patients harbored both the c.376T and the c.421A genotypes on distinct alleles. Gefitinib-related interstitial lung disease and severe diarrhea were noted in neither of the two patients.
In this Japanese population, we did not find an evident association between ABCG2 polymorphisms, c.376C > T and c.421C > A, and susceptibility to gefitinib-induced adverse effects.

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    • "These studies suggest that patients with reduced ABCG2/BCRP activity arising from a genetic variation might be at increased risk of gefitinib-induced diarrhea, and these genetic markers should be considered in the optimization of NSCLC treatments with gefitinib. However, no clear association was reported between the 421C.A SNP of ABCG2/BCRP and a susceptibility to gefitinib-induced adverse effects in a Japanese population.134 The skin toxicity of gefitinib is also reported to be unrelated to this SNP.103 "
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    • "This protein modulates the absorption, metabolism and toxicity of numerous drugs and xenobiotics, and causes multidrug resistance in cancer [5], [6], [7], [8], [9], [10], [11], [12]. Polymorphic variants or nonsense mutations of ABCG2 were found to be associated with interindividual variability in drug response to anticancer chemotherapy and the outcome of psoriasis or multiple sclerosis treatments [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Recently, a significant disease-association for a polymorphic ABCG2 variant (resulting in ABCG2-Q141K) has been observed in gout [24], [25], [26], [27], [28]. "
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