Han Seungmin, Lim Kwang Suk, Blackburn Brody J, Yun Jina, Putnam Charles W, Bull David A, Won Young-Wook
Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, AZ 85724, USA.
Department of Biotechnology and Bioengineering, College of Art, Culture and Engineering, Kangwon National University, Chuncheon 24341, Korea.
Pharmaceutics. 2022 Aug 16;14(8):1707. doi: 10.3390/pharmaceutics14081707.
DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.
DNA拓扑异构酶是稳定DNA超螺旋和解决缠结的必需酶。在过去20年里，拓扑异构酶抑制剂已被广泛用作抗癌药物。由于喜树碱及其衍生物作为捕获TOP1切割复合物的拓扑异构酶I（TOP1）抑制剂具有选择性，它们是很有前景的抗癌药物。为了通过靶向肿瘤增加TOP1抑制剂在癌细胞中的积累，已经开发并上市了TOP1抑制剂抗体-药物偶联物（TOP1-ADC）。与典型的抗癌ADC（如T-DM1）相比，一些TOP1-ADC显示出增强的治疗效果。在这里，我们综述了各种基于喜树碱的TOP1抑制剂以及TOP1-ADC的最新进展。然后我们提出了TOP1-ADC设计和构建的关键点。最后，我们讨论了有前景的联合策略，包括新开发的使TOP1-ADC治疗潜力最大化的方法。
