Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer
Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer
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DOI：
10.1007/s00280-009-1211-6
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发表时间：
2010-09-01
影响因子：
3
通讯作者：
Imai, Yasuo
中科院分区：
文献类型：
--
作者：
Akasaka, Keiichi;Kaburagi, Takayuki;Imai, Yasuo
ABCG2是一种半大小的atp结合盒转运体，参与细胞吉非替尼转运。据报道，c.421C bbbba ABCG2基因多态性与白人非小细胞肺癌患者吉非替尼诱导的腹泻有关。由于导致p.Q141K取代的c.421C > A ABCG2在亚洲人群中更为普遍，因此我们在日本患者中研究了吉非替尼诱导的不良反应与这种功能多态性之间的推定关系。c.376C > T导致截断，无功能的ABCG2，也进行了研究。对75例口服吉非替尼250mg /天治疗的非小细胞肺癌患者的ABCG2基因多态性进行了评估，结果与治疗相关的不良反应相关。40例（53.3%）患者在至少一个等位基因上携带c.421A ABCG2，而其余35例（46.7%）患者为c.421C bbc0 a野生型。吉非替尼相关腹泻或其他不良反应发生频率组间无显著差异。此外，本研究中唯一一名c.421A等位基因纯合的患者没有受到吉非替尼引起的腹泻或间质性肺疾病的影响。2例（2.7%）患者存在c.376T等位基因杂合。其中一名患者在不同的等位基因上同时携带c.376T和c.421A基因型。两例患者均未出现吉非替尼相关的间质性肺疾病和严重腹泻。在这个日本人群中，我们没有发现ABCG2多态性、c.376C > T和c.421C > A与吉非替尼诱导的不良反应易感性之间的明显关联。
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.