Group of Molecular Oncology, Molecular Biology and Biochemistry Research Center, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Barcelona, Spain.
Clin Cancer Res. 2010 Apr 15;16(8):2375-82. doi: 10.1158/1078-0432.CCR-09-3275. Epub 2010 Apr 6.
Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond.
Here we used microarray analysis of a panel of 30 colorectal cancer cell lines and immunohistochemistry to identify and validate a new biomarker of response to irinotecan.
A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair. Moreover, using an isogenic in vitro system deficient in APTX, we show that aprataxin directly regulates the cellular sensitivity to camptothecin, suggesting that it could be used to predict patient response to irinotecan. We constructed a tissue microarray containing duplicate tumor samples from 135 patients that received irinotecan for the treatment of advanced colorectal cancer. Immunohistochemical assessment of the tumor levels of aprataxin showed a significant association with treatment response and patient survival. Patients with low aprataxin had longer progression-free (9.2 versus 5.5 months; P = 0.03) and overall survival (36.7 versus 19.0 months; P = 0.008) than patients with high tumor aprataxin. No associations were found between coding APTX variants and aprataxin levels or camptothecin sensitivity.
These results show that aprataxin tumor levels can be used to identify patients with low probability of response to irinotecan-based therapy who are ideal candidates to receive treatment with alternative agents in an attempt to improve patient survival.
伊立替康（CPT11）治疗可显著改善结直肠癌患者的生存率，并且常被单独或与其他药物联合用于这些患者的治疗。然而，只有 20%至 30%的患者对伊立替康有客观反应，因此非常需要新的分子标志物来识别那些不太可能有反应的患者亚群。
在这里，我们使用 30 种结直肠癌细胞系的微阵列分析和免疫组织化学来鉴定和验证伊立替康反应的新生物标志物。
伊立替康敏感性与参与 DNA 修复的组氨酸三联体域超家族蛋白 aprataxin 的表达之间存在良好的相关性。此外，我们使用 APTX 缺陷的体外同基因系统，表明 aprataxin 直接调节细胞对喜树碱的敏感性，提示它可用于预测患者对伊立替康的反应。我们构建了一个包含 135 例接受伊立替康治疗晚期结直肠癌患者的肿瘤样本的组织微阵列。免疫组织化学评估肿瘤 aprataxin 的水平与治疗反应和患者生存之间存在显著相关性。低 aprataxin 水平的患者无进展生存期（9.2 个月对 5.5 个月；P = 0.03）和总生存期（36.7 个月对 19.0 个月；P = 0.008）均长于高肿瘤 aprataxin 水平的患者。编码 APTX 变异体与 aprataxin 水平或喜树碱敏感性之间没有相关性。
这些结果表明，肿瘤 aprataxin 水平可用于识别对伊立替康为基础的治疗反应可能性低的患者，这些患者是接受替代药物治疗以提高患者生存率的理想候选者。
