Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):469-76. doi: 10.1016/j.ijrobp.2013.02.015. Epub 2013 Mar 26.
Poly(ADP-ribose) polymerase plays a critical role in the recognition and repair of DNA single-strand breaks and double-strand breaks (DSBs). ABT-888 is an orally available inhibitor of this enzyme. This study seeks to evaluate the use of ABT-888 combined with chemotherapy and radiation therapy (RT) in colorectal carcinoma models.
RT clonogenic assays were performed on HCT116 and HT29 cells treated with 5-fluorouracil, irinotecan, or oxaliplatin with or without ABT. The surviving fraction at 2 Gy and dose-modifying factor at 10% survival were analyzed. Synergism was assessed by isobologram analysis for combination therapies. γH2AX and neutral comet assays were performed to assess the effect of therapy on DSB formation/repair. In vivo assessments were made by use of HCT116 cells in a xenograft mouse model. Tumor growth delay was measured at a volume of 500 mm(3).
Both lines were radiosensitized by ABT alone, and ABT further increased chemotherapy dose-modifying factors to the 1.6 to 1.8 range. All combinations were synergistic (combination indices <0.9). ABT treatment significantly increased DSB after RT (γH2AX, 69% vs 43%; P=.017) and delayed repair. We found tumor growth delays of 7.22 days for RT; 11.90 days for RT and ABT; 13.5 days for oxaliplatin, RT, and ABT; 14.17 days for 5-fluorouracil, RT, and ABT; and 23.81 days for irinotecan, RT, and ABT.
ABT-888 radiosensitizes at similar or higher levels compared with classic chemotherapies and acts synergistically with these chemotherapies to enhance RT effects. In vivo confirmation of these results indicates a potential role for combining its use with existing chemoradiation regimens.
聚（ADP-核糖）聚合酶在识别和修复 DNA 单链断裂和双链断裂（DSB）中发挥关键作用。ABT-888 是一种可口服的该酶抑制剂。本研究旨在评估 AB丁-888 联合化疗和放疗（RT）在结直肠癌模型中的应用。
用 5-氟尿嘧啶、伊立替康或奥沙利铂处理 HCT116 和 HT29 细胞，进行 RT 集落形成测定，并用或不用 AB丁处理。分析 2 Gy 时的存活分数和 10%存活时的剂量修饰因子。用等效应线分析评估联合治疗的协同作用。用 γH2AX 和中性彗星试验评估治疗对 DSB 形成/修复的影响。在异种移植小鼠模型中使用 HCT116 细胞进行体内评估。以体积 500 mm(3) 测量肿瘤生长延迟。
ABT 单独处理两条线均能放射增敏，ABT 进一步将化疗剂量修饰因子提高到 1.6 到 1.8 范围。所有组合均具有协同作用（组合指数<0.9）。ABT 治疗显著增加了 RT 后的 DSB（γH2AX，69%比 43%；P=.017）并延迟了修复。我们发现 RT 的肿瘤生长延迟为 7.22 天；RT 和 AB丁为 11.90 天；奥沙利铂、RT 和 AB丁为 13.5 天；5-氟尿嘧啶、RT 和 AB丁为 14.17 天；伊立替康、RT 和 AB丁为 23.81 天。
ABT-888 的放射增敏作用与经典化疗相似或更高，并与这些化疗药物协同作用，增强 RT 效果。体内对这些结果的证实表明，将其与现有的放化疗方案联合使用具有潜在作用。
