Analytical Cytology Laboratory, Shantou University Medical College, Shantou, Guangdong, PR China.
Int J Hyg Environ Health. 2010 Mar;213(2):140-5. doi: 10.1016/j.ijheh.2010.01.004. Epub 2010 Mar 1.
Among the cancer patient population, resistance to therapy is a major cause for therapeutic failure and for human sufferings, especially for the cancer with poor prognosis. Therefore, finding factors that contribute to drug resistance is a major research interest. In this study, we have investigated whether polymorphisms in genes that control import/export of drugs (MDR1) and that repair DNA adducts (ERCC1) are involved with drug resistance in non-small cell lung cancer (NSCLC) patients. We have recruited 95 patients with advanced NSCLC (stages IIIB-IV) who were specifically treated with platinum-based chemotherapy. We used the ligase detection reactions assay (LDR) to detect polymorphisms in ERCC1 118C/T, and MDR1 2677T/A, E1/-129T/C, and C3435T in peripheral blood lymphocytes from the patients. The haplotype of MDR1 gene single nucleotide polymorphisms (SNPs) were analyzed using the SHEsis software platform on line. We found that none of the single polymorphisms was associated with treatment response or related toxicity. However, patients carrying at least one variant MDR1 2677 T allele was associated with a significantly increased risk of drug resistance (OR=1.844, 95% CI=1.01-3.53, P=0.04) but also with a significantly increased risk of gastrointestinal toxicity (P=0.03) but not hemato-, hepato- or nephro-toxicities. Moreover, we analyzed the haplotypes of the three polymorphisms in MDR1. The patients harboring the E1/-129T-2677T-3435C haplotype had a significantly better response to chemotherapy compared with those having the other haplotypes (P=0.02, 95% CI=1.20-25.87), and a marginally significant association with increased risk of gastrointestinal toxicity (P=0.02, 95% CI=1.15-3.88). Our results suggested that gene polymorphisms in MDR1G2677T/A may be a predictive marker of platinum-based treatment response and of secondary effects, especially gastrointestinal toxicity for advanced NSCLC patients.
在癌症患者群体中，对治疗的耐药性是治疗失败和人类痛苦的主要原因，尤其是对于预后不良的癌症。因此，寻找导致耐药性的因素是一个主要的研究兴趣。在这项研究中，我们研究了控制药物进出口的基因（MDR1）和修复 DNA 加合物的基因（ERCC1）中的多态性是否与非小细胞肺癌（NSCLC）患者的耐药性有关。我们招募了 95 名晚期 NSCLC（IIIb-IV 期）患者，他们专门接受了铂类化疗。我们使用连接酶检测反应（LDR）检测了患者外周血淋巴细胞中 ERCC1 118C/T 和 MDR1 2677T/A、E1/-129T/C 和 C3435T 的多态性。使用在线 SHEsis 软件平台分析 MDR1 基因单核苷酸多态性（SNP）的单倍型。我们发现，没有一个单一的多态性与治疗反应或相关毒性有关。然而，携带至少一个变异 MDR1 2677 T 等位基因的患者发生耐药的风险显著增加（OR=1.844，95%CI=1.01-3.53，P=0.04），且胃肠道毒性的风险也显著增加（P=0.03），但不增加血液毒性、肝毒性或肾毒性。此外，我们分析了 MDR1 中三个多态性的单倍型。与其他单倍型相比，携带 E1/-129T-2677T-3435C 单倍型的患者对化疗的反应明显更好（P=0.02，95%CI=1.20-25.87），且与胃肠道毒性风险增加有显著关联（P=0.02，95%CI=1.15-3.88）。我们的结果表明，MDR1G2677T/A 基因多态性可能是预测晚期 NSCLC 患者基于铂类治疗反应和次要作用（特别是胃肠道毒性）的标志物。
