Cancer Research UK-Medical Research Council, Oncology Department, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom.
Antioxid Redox Signal. 2013 Mar 10;18(8):851-73. doi: 10.1089/ars.2011.4203. Epub 2012 Sep 5.
Apart from surgical approaches, the treatment of cancer remains largely underpinned by radiotherapy and pharmacological agents that cause damage to cellular DNA, which ultimately causes cancer cell death. DNA polymerases, which are involved in the repair of cellular DNA damage, are therefore potential targets for inhibitors for improving the efficacy of cancer therapy. They can be divided, according to their main function, into two groups, namely replicative and nonreplicative enzymes. At least 15 different DNA polymerases, including their homologs, have been discovered to date, which vary considerably in processivity and fidelity. Many of the nonreplicative (specialized) DNA polymerases replicate DNA in an error-prone fashion, and they have been shown to participate in multiple DNA damage repair and tolerance pathways, which are often aberrant in cancer cells. Alterations in DNA repair pathways involving DNA polymerases have been linked with cancer survival and with treatment response to radiotherapy or to classes of cytotoxic drugs routinely used for cancer treatment, particularly cisplatin, oxaliplatin, etoposide, and bleomycin. Indeed, there are extensive preclinical data to suggest that DNA polymerase inhibition may prove to be a useful approach for increasing the effectiveness of therapies in patients with cancer. Furthermore, specialized DNA polymerases warrant examination of their potential use as clinical biomarkers to select for particular cancer therapies, to individualize treatment for patients.
除了手术方法外，癌症的治疗在很大程度上仍然依赖于放射治疗和药理制剂，这些方法会对细胞 DNA 造成损伤，最终导致癌细胞死亡。因此，参与细胞 DNA 损伤修复的 DNA 聚合酶是提高癌症治疗效果的抑制剂的潜在靶点。根据其主要功能，它们可以分为两类，即复制酶和非复制酶。迄今为止，已经发现至少有 15 种不同的 DNA 聚合酶，包括它们的同源物，它们在进程和保真度上差异很大。许多非复制（专门）的 DNA 聚合酶以易错的方式复制 DNA，并且已经证明它们参与多种 DNA 损伤修复和耐受途径，这些途径在癌细胞中经常异常。涉及 DNA 聚合酶的 DNA 修复途径的改变与癌症的存活以及对放射治疗或常规用于癌症治疗的细胞毒性药物（特别是顺铂、奥沙利铂、依托泊苷和博来霉素）的治疗反应有关。事实上，有大量的临床前数据表明，DNA 聚合酶抑制可能被证明是提高癌症患者治疗效果的一种有用方法。此外，专门的 DNA 聚合酶值得研究它们作为临床生物标志物的潜在用途，以选择特定的癌症治疗方法，为患者进行个体化治疗。
