Inotuzumab ozogamicin (IO) 是一种治疗复发或难治性急性淋巴细胞白血病 (RR)-(ALL) 的新型治疗药物，是一种与加利车霉素缀合的人源化抗分化簇 (CD) 22 单克隆抗体，可引起 DNA 单链和双链链断裂。尽管与传统化疗相比，IO 的疗效显着提高，但 RR-ALL 的预后仍然较差，凸显需要更有效的治疗策略。本研究探讨了使用聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕尼或他拉佐帕尼抑制 DNA 损伤修复对增强 IO 对 B-ALL 细胞体外抗肿瘤作用的作用。 Reh、Philadelphia (Ph)-B-ALL 和 SUP-B15 Ph B-ALL 细胞系用于实验。两种细胞系均为~90% CD22。 Reh 和 SUP-B15 细胞的 IO 半数抑制浓度 (IC50) 值分别为 5.3 和 49.7 ng/ml。 IO 与最低毒性浓度的奥拉帕尼或他拉佐帕尼组合的 IC50 值对于 Reh 细胞分别为 0.8 和 2.9 ng/ml，对于 SUP-B15 细胞分别为 36.1 和 39.6 ng/ml。 Reh 细胞的 IO 与奥拉帕尼和他拉佐帕尼的组合指数分别为 0.19 和 0.56，SUP-B15 细胞的 IO 组合指数为 0.76 和 0.89，表明所有组合均具有协同作用。此外，添加最低毒性浓度的 PARP 抑制剂会增强 IO 诱导的细胞凋亡。碱性彗星试验可定量 DNA 链断裂量，用于研究 IO 给药后 1 小时观察到的 DNA 损伤在 6 小时后修复的程度，反映 DNA 链断裂的成功修复。然而，在 IO 联合奥拉帕尼或他拉佐帕尼给药后 6 小时，DNA 链断裂持续存在，表明 PARP 抑制剂抑制了修复过程。添加奥拉帕尼或他拉佐帕尼可通过抑制 PARP 来抑制 DNA 链断裂修复，从而协同 IO 的抗肿瘤作用。

Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)‑(ALL), is a humanized anti‑cluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single‑ and double‑strand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RR‑ALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADP‑ribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on B‑ALL cells in vitro. The Reh, Philadelphia (Ph)‑B‑ALL and the SUP‑B15 Ph+ B‑ALL cell lines were used for experiments. Both cell lines were ~90% CD22+. The half‑maximal inhibitory concentration (IC50) values of IO were 5.3 and 49.7 ng/ml for Reh and SUP‑B15 cells, respectively. The IC50 values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUP‑B15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUP‑B15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IO‑induced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.