Abstract：
The effectiveness of radiotherapy depends on the sensitivities of \'normal\' and cancer cells to the administered radiation dose. Increasing the radiosensitivity of cancers by inhibiting DNA damage repair is a goal of much current research, however success depends on avoiding concomitant sensitization of normal tissues inevitably irradiated during therapy. In this study we investigated the mechanisms of radiosensitization for DNA-PK and PARP inhibitors by examining the impacts on proliferating vs quiescent cell populations. Experiments were performed in BRCA1/2null and wild-type parental cancer models in vitro and in vivo. Overall AZD7648 has greater radiosensitizing activity relative to Olaparib, with BRCA2-deficient models showing the greatest sensitivity. However, DNA-PK inhibitor AZD7648 also produced greater toxicity in all irradiated mice. While both DNA-PK and PARP inhibition sensitizes wild type tumor cells to radiation, in BRCA1/2 deficient cells PARP inhibition by Olaparib had limited radiosensitization capacity. Quiescent cells are more radioresistant than proliferating cells, and these were also effectively sensitized by AZD7648 while Olaparib was unable to increase radiation-induced cell kill, even in BRCA1/2null cells. These findings underscore the distinct mechanisms of radiosensitization for DNA-PK and PARP inhibitors. While DNA-PK inhibitors are able to target both proliferating and non-proliferating tumor cells for greater overall anti-cancer benefit, their application is limited by exacerbation of normal tissue toxicities. Conversely, PARP inhibitors exhibit selective activity for proliferating cells, providing a mechanism for targeting activity to cancers, but due to poor activity in non-proliferating cells they have an overall reduced impact on tumor growth control. This study highlights the importance of creating a therapeutic ratio with DNA damage repair inhibition radiation sensitizing strategies.
摘要：
放疗的有效性取决于“正常”细胞和癌细胞对所施用的辐射剂量的敏感性。通过抑制DNA损伤修复来提高癌症的放射敏感性是当前许多研究的目标。然而，成功取决于避免在治疗期间不可避免地照射正常组织的伴随致敏。在这项研究中，我们通过检查对增殖和静止细胞群体的影响，研究了DNA-PK和PARP抑制剂的放射增敏机制。在体外和体内在BRCA1/2null和野生型亲本癌症模型中进行实验。总体上，AZD7648相对于Olaparib具有更大的放射增敏活性，BRCA2缺陷模型显示出最大的敏感性。然而,DNA-PK抑制剂AZD7648在所有照射的小鼠中也产生更大的毒性。虽然DNA-PK和PARP抑制使野生型肿瘤细胞对辐射敏感，在BRCA1/2缺陷型细胞中,奥拉帕尼对PARP的抑制具有有限的放射增敏能力.静止细胞比增殖细胞更耐辐射，这些也被AZD7648有效致敏，而Olaparib无法增加辐射诱导的细胞杀伤，即使在BRCA1/2null单元格中。这些发现强调了DNA-PK和PARP抑制剂的放射增敏的不同机制。虽然DNA-PK抑制剂能够靶向增殖和非增殖肿瘤细胞，以获得更大的整体抗癌益处，它们的应用受到正常组织毒性恶化的限制。相反，PARP抑制剂对增殖细胞具有选择性活性，提供了一种靶向癌症的机制，但是由于非增殖细胞的活性差，它们对肿瘤生长控制的影响总体上降低了。这项研究强调了用DNA损伤修复抑制辐射致敏策略创建治疗比例的重要性。
