Toxicogenomics Unit, National Institute of Public Health, Srobarova 48, Prague 10, 100 42 Czech Republic.
Mutagenesis. 2012 Mar;27(2):187-96. doi: 10.1093/mutage/ger075.
Worldwide, colorectal cancer (CRC) is the third most common cancer, with the highest mortality rates occurring in Central Europe. The use of chemotherapy to treat CRC is limited by the inter-individual variability in drug response and the development of cancer cell resistance. ATP-binding cassette (ABC) transporters play a crucial role in the development of resistance by the efflux of anticancer agents outside of cancer cells. The aim of this study was to explore transcript levels of all human ABCs in tumours and non-neoplastic control tissues from CRC patients collected before the first line of treatment by 5-fluorouracil (5-FU)-containing regimen. The prognostic potential of ABCs was evaluated by the correlation of transcript levels with clinical factors. Relations between transcript levels of ABCs in tumours and chemotherapy efficacy were also addressed. The transcript profile of all known human ABCs was assessed using real-time polymerase chain reaction with a relative standard curve. The majority of the studied ABCs were down-regulated or unchanged between tumours and control tissues. ABCA12, ABCA13, ABCB6, ABCC1, ABCC2 and ABCE1 were up-regulated in tumours versus control tissues. Transcript levels of ABCA12, ABCC7 and ABCC8 increased in direction from colon to rectum. Additionally, transcript levels of ABCB9, ABCB11, ABCG5 and ABCG8 followed the reverse significant trend, i.e. a decrease in direction from colon to rectum. The transcript level of ABCC10 in tumours correlated with the grade (P = 0.01). Transcript levels of ABCC6, ABCC11, ABCF1 and ABCF2 were significantly lower in non-responders to palliative chemotherapy in comparison with responders. The disease-free interval of patients treated by adjuvant chemotherapy was significantly shorter in patients with low transcript levels of ABCA7, ABCA13, ABCB4, ABCC11 and ABCD4. In conclusion, ABCC11 may be a promising candidate marker for a validation study on 5-FU therapy outcome.
在全球范围内，结直肠癌（CRC）是第三大常见癌症，中欧地区的死亡率最高。由于药物反应的个体间差异以及癌细胞耐药性的发展，化疗治疗 CRC 受到限制。ATP 结合盒（ABC）转运蛋白通过将抗癌药物外排到癌细胞外，在耐药性的发展中起着至关重要的作用。本研究旨在通过含有 5-氟尿嘧啶（5-FU）方案的一线治疗前，从 CRC 患者的肿瘤和非肿瘤对照组织中探索所有人类 ABC 的转录水平。通过将转录水平与临床因素相关联，评估 ABC 的预后潜力。还研究了肿瘤中 ABC 的转录水平与化疗疗效之间的关系。使用实时聚合酶链反应和相对标准曲线评估所有已知人类 ABC 的转录谱。在肿瘤与对照组织之间，大多数研究的 ABC 下调或不变。ABCA12、ABCA13、ABCB6、ABCC1、ABCC2 和 ABCE1 在肿瘤中上调。ABCA12、ABCC7 和 ABCC8 的转录水平从结肠到直肠方向增加。此外，ABCB9、ABCB11、ABCG5 和 ABCG8 的转录水平遵循相反的显著趋势，即从结肠到直肠方向减少。ABCC10 在肿瘤中的转录水平与肿瘤分级相关（P=0.01）。与姑息化疗反应者相比，无反应者的 ABCC6、ABCC11、ABCF1 和 ABCF2 的转录水平显著降低。接受辅助化疗的患者，其 ABCA7、ABCA13、ABCB4、ABCC11 和 ABCD4 转录水平较低的患者无病间隔明显缩短。总之，ABCC11 可能是验证 5-FU 治疗结果的候选标志物。
