Venkatachalam Annapoorna, Kaufmann Scott H
Division of Oncology Research, Department of Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
Division of Oncology Research, Department of Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.
J Mol Biol. 2025 Aug 21:169401. doi: 10.1016/j.jmb.2025.169401.
As an enzyme that relaxes torsionally strained DNA, TOP1 is present in all nucleated human somatic cells. Even though this ubiquity makes TOP1 an unlikely anticancer drug target, six FDA-approved antineoplastic treatments, including two approved in the past five years, and a variety of experimental agents inhibit the TOP1 catalytic cycle. To provide insight into the continuing effort to develop TOP1-directed agents, here we briefly review the biology of TOP1, the cellular effects of stabilizing TOP1-DNA covalent complexes, mechanisms of resistance to TOP1 poisons, and strategies to overcome this resistance before describing efforts to develop TOP1 catalytic inhibitors as well as an exciting new generation of tumor targeting nanoparticles and antibody-drug conjugates that deliver TOP1-directed agents to cancers at high concentrations while sparing normal tissues. When paired with inhibitors of DNA damage response pathways, epigenetic therapies, or immune modulators, these new TOP1-directed agents promise to improve the therapy of a wide range of solid tumors.
作为一种可松弛扭转应力DNA的酶，TOP1存在于所有有核人类体细胞中。尽管这种普遍存在使得TOP1不太可能成为抗癌药物靶点，但六种FDA批准的抗肿瘤治疗方法（包括过去五年内批准的两种）以及多种实验性药物均可抑制TOP1催化循环。为深入了解开发TOP1导向药物的持续努力，在此我们简要回顾TOP1的生物学特性、稳定TOP1-DNA共价复合物的细胞效应、对TOP1毒物的耐药机制以及克服这种耐药性的策略，然后再描述开发TOP1催化抑制剂的努力，以及令人兴奋的新一代肿瘤靶向纳米颗粒和抗体药物偶联物，它们可将TOP1导向药物高浓度递送至癌症部位，同时 sparing正常组织。当与DNA损伤反应途径抑制剂、表观遗传疗法或免疫调节剂联合使用时，这些新型TOP1导向药物有望改善多种实体瘤的治疗效果。
