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是与细胞吉非替尼转运有关的半尺寸ATP结合盒转运蛋白。据报道，C421A ABCG2基因变体与非小细胞肺癌的高加索人患者中吉非替尼诱导的腹泻有关。 C421A ABCG2导致Q141K替代，在亚洲人群中更为普遍。因此，在75例用吉非替尼250 mg/d治疗的日本非小细胞肺癌的日本患者中，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推定关系。还研究了C376T，导致截短的非功能ABCG2。至少一个等位基因上有41名（54.7％）患者在至少一个等位基因上携带了376T或421A ABCG2，而其余的34例（45.3％）的ABCG2是野生型。在吉非替尼相关的腹泻或其他不良反应的频率上未观察到显着的群体差异。接下来，建立了表达野生型（DLD-1/WT）或141K突变体ABCG2（DLD-1/Q141K）的DLD-1结肠癌细胞，以研究对ABCG2-基层药物Gefitinib，Gefitinib和SN-38的维特罗细胞敏感性。尽管ABCG2 mRNA水平相似，但在DLD-1/Q141K细胞中，DLD-1/Q141K细胞的ABCG2表达比DLD-1/WT细胞低得多。与DLD-1/Q141K细胞相比，DLD-1/WT细胞获得了对SN-38的耐药性，但与亲本细胞相比，未获得吉非替尼的耐药性。体外数据还表明，在结肠衍生的细胞中，ABCG2在Gefitinib的毒性中仅具有有限的作用，而SN-38的作用有限。