Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, DK-2730 Herlev, Denmark.
Section of Molecular Disease Biology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Int J Mol Sci. 2017 Sep 7;18(9):1926. doi: 10.3390/ijms18091926.
One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients.
Few studies have evaluated the association between gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan.
The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed.
拓扑异构酶-1 抑制剂伊立替康是转移性结直肠癌（mCRC）患者常规使用的主要化疗药物之一。然而，其应用受到固有或必然产生的耐药性的限制。ATP 结合盒（ABC）转运蛋白 ABCG2/乳腺癌耐药蛋白（BRCP）通过其对异生物质清除的功能，可能在伊立替康耐药中发挥重要作用。为了评估 ABCG2 测量的临床意义，我们在此回顾了与 CRC 患者伊立替康治疗相关的 ABCG2 相关的当前文献。
很少有研究评估基因或蛋白表达与 CRC 患者预后之间的关系。报道的结果存在差异。这些差异可能是由于免疫组织化学研究中对结果解释的使用不同标准。只有一项大型研究评估了 ABCG2 蛋白表达与 mCRC 伊立替康疗效的关系（CAIRO 研究，=566）。该研究未能证明原发肿瘤中 ABCG2 蛋白表达与基于伊立替康的治疗反应之间存在任何相关性。我们最近提出了如何评估 ABCG2 免疫反应模式的问题，并且 CAIRO 研究的结果可能受到使用与我们提出的方案不同的评分方案的影响。相比之下，我们最近对 580 名 III 期原发性 CRC 患者（来自随机 PETACC-3 研究的亚组）的 mRNA 表达进行的探索性研究表明，高肿瘤组织 mRNA 表达可能预示伊立替康疗效不佳。
ABC-G2 在预测 CRC 中临床伊立替康敏感性/耐药性方面的生物学作用尚不确定。特别是，需要确定 ABCG2 细胞定位的意义。有关 mRNA 表达和辅助伊立替康疗效预测的数据仍然很少，需要进一步证实。
