以恶性细胞、内皮细胞和间充质干细胞组成的多细胞球体作为体外模型，研究了通过药理学调节DNA修复通路来增强DNA损伤药物的作用。将拓扑替尼、特尔巴替丁和替莫唑胺等DNA损伤药物与PARP（奥拉帕尼布或塔拉索帕尼布）、ATM（遗传性毛细血管扩张症; AZD-1390）、ATR（遗传性毛细血管扩张症和辐射敏感性蛋白; berzosertib或elimusertib）和DNA-PK（依赖性DNA蛋白激酶; nedisertib或VX-984）的不同抑制剂结合。测试了一系列临床可达浓度，最高不超过临床Cmax（如果已知）。从多细胞球体对各种DNA修复抑制剂的组合反应中，可以明显看出替莫唑胺、拓扑替尼和特尔巴替丁引起的DNA损伤类型是不同的。虽然大多数组合结果为附加细胞毒性，但观察到特莫唑胺与PARP抑制剂的组合以及ATM抑制剂AZD-1390与拓扑替尼或特尔巴替丁的组合具有协同活性。这些发现可能为进一步研究抗癌药物组合的选择提供指导。肿瘤细胞的DNA损伤应答可以影响DNA损伤性抗癌药物的临床疗效。对多细胞肿瘤球体进行了通过药理学调节DNA修复通路来增强DNA损伤药物效力的评估。虽然大多数组合显示附加细胞毒性，但对几种药物组合观察到了协同细胞毒性。© 2023 The Authors; Published by the American Association for Cancer Research.

Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical Cmax, if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation.Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.© 2023 The Authors; Published by the American Association for Cancer Research.