Effects of functional ABCG2 polymorphisms on the sensitivities/adverse effects of gefitinib in patients with non-small-cell lung cancer

功能性ABCG2多态性对吉非替尼治疗非小细胞肺癌敏感性/不良反应的影响

基本信息

批准号：
20590372
负责人：
IMAI Yasuo
金额：
$ 1.83万
依托单位：
Dokkyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590372/
关键词：
分子病理抗癌剤感受性・副作用発症予測遺伝子診断病理学

项目摘要

ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the C421A ABCG2 gene variant was associated with gefitinib-induced diarrhea in Caucasian patients with non-small cell lung cancer. C421A ABCG2, resulting in Q141K substitution, is more prevalent in Asian populations. Therefore, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in 75 Japanese patients with non-small cell lung cancer treated with gefitinib 250 mg/d orally. C376T, resulting in truncated, non-functional ABCG2, was also investigated. Forty one (54.7%) patients harbored 376T or 421A ABCG2 on at least one allele, while the remaining 34 (45.3%) were wild type for ABCG2. No significant group differences were observed in frequency of gefitinib-related diarrhea or other adverse effects. Next, DLD-1 colon cancer cells expressing wild-type (DLD-1/WT) or 141K mutant ABCG2 (DLD-1/Q141K) were established for investigation of in-vitro cell sensitivity to the ABCG2-substrate drugs, gefitinib and SN-38. ABCG2 expression was much lower in DLD-1/Q141K cells than in DLD-1/WT cells, despite similar ABCG2 mRNA levels. DLD-1/WT cells acquired more resistance to SN-38 than did DLD-1/Q141K cells, but neither cell line acquired gefitinib resistance compared with parental cells. In-vitro data also suggested that ABCG2 has only a limited role in toxicity of gefitinib, but not SN-38, in colon-derived cells.

ABCG2 是一种半大小 ATP 结合盒转运蛋白，参与细胞吉非替尼转运。据报道，C421A ABCG2 基因变异与白人非小细胞肺癌患者吉非替尼引起的腹泻有关。 C421A ABCG2 导致 Q141K 取代，在亚洲人群中更为普遍。因此，我们在 75 名接受吉非替尼 250 mg/d 口服治疗的日本非小细胞肺癌患者中研究了吉非替尼引起的不良反应与这种功能多态性之间的假定关系。还研究了导致截短的、无功能的 ABCG2 的 C376T。 41 名 (54.7%) 患者至少在一个等位基因上携带 376T 或 421A ABCG2，而其余 34 名 (45.3%) 患者为 ABCG2 野生型。吉非替尼相关腹泻或其他不良反应的发生频率没有观察到显着的组间差异。接下来，建立表达野生型 (DLD-1/WT) 或 141K 突变 ABCG2 (DLD-1/Q141K) 的 DLD-1 结肠癌细胞，用于研究体外细胞对 ABCG2 底物药物吉非替尼和 SN 的敏感性。 -38。尽管 ABCG2 mRNA 水平相似，但 DLD-1/Q141K 细胞中的 ABCG2 表达远低于 DLD-1/WT 细胞。 DLD-1/WT 细胞比 DLD-1/Q141K 细胞获得更多的 SN-38 耐药性，但与亲本细胞相比，这两种细胞系均未获得吉非替尼耐药性。体外数据还表明，ABCG2 对吉非替尼的毒性作用有限，但对结肠来源细胞中的 SN-38 没有作用。