Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.
Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain.
Eur J Clin Invest. 2015 Dec;45(12):1325-32. doi: 10.1111/eci.12557. Epub 2015 Nov 20.
Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS).
Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells.
The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P < 0·05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P < 0·01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41·71, P = 0·033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1-overexpressing breast cancer cells.
A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti-angiogenic drugs.
目前，癌症的抗血管生成策略尚无预测性生物标志物，但抗血管生成药物的反应与治疗引起的高血压有关。因此，本研究探讨了肾素-血管紧张素系统（RAS）某些成分的遗传多态性与临床的相关性。
从 95 名接受贝伐单抗治疗的转移性乳腺癌或结直肠癌患者的外周血中分离基因组 DNA，采用 RT-PCR 方法对 AGTR1-A1166C(rs5186)、AGT-M235T(rs699) 单核苷酸多态性和 ACE I/D(rs4646994)多态性进行基因分型。采用 ELISA 试剂盒分析循环血管内皮生长因子和血管紧张素转换酶（ACE）水平。用过表达 AGTR1 的乳腺癌细胞原位异种移植小鼠来检测贝伐单抗的抗肿瘤活性。
ACE IN/IN 基因型与疾病进展率较高相关，与 DEL/IN 和 DEL/DEL 基因型相比（36% vs. 11.1%，P < 0.05）。同样，AGTR1-1166A/A 基因型与疾病进展率较高相关，与 AGTR1-1166A/C 和 AGTR1-1166C/C 基因型相比（24.4% vs. 2.7%，P < 0.01）。ACE IN/IN 基因型与治疗失败时间较短相关，与 ACE IN/DEL 和 ACE DEL/DEL 基因型相比（14 周 vs. 41.71，P = 0.033），而循环 ACE 水平与贝伐单抗治疗反应较好相关。此外，体内实验表明，源自 AGTR1 过表达乳腺癌细胞的肿瘤对贝伐单抗的抗肿瘤活性显著提高。
ACE-血管紧张素-II-AGTR1 轴的活性较高与对贝伐单抗的反应较好相关，支持 RAS 可能是抗血管生成药物反应的潜在预测性生物标志物的重要来源。
