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摘要
DNA损伤药物在癌症中存在两个主要问题:治疗耐药性和副作用都可能与以癌症治疗为目的的DNA修复相关。博来霉素(BLM)通过链断裂,碱基损失和3’磷酸(3''PG)等多种途径修复残留诱导复杂的DNA损伤,但通常3''PGs必须用酪酰胺-DNA磷酸二酯酶1(Tdp1)处理3-OH端。因此,针对Tdp1可以提高GLM抗癌治疗效果。丝裂霉素C(MMC)产生的各种DNA加合物,比如:链间交联(ICLS)和着色性干皮病(XP)蛋白质,这些蛋白质包括XPG,XPE和XPF在ICL修复的初始阶段是至关重要的,所以它们可以通过靶向抑制剂来增强MMC在肿瘤细胞中的毒性。虽然核苷酸切除修复(NER)需要这些蛋白质,但它们的活性降低可能在正常细胞中并不会有致命的影响,因为几乎所有的NER底物都可以通过其他途径修复。4链DNA主要产生于鸟嘌呤四链体(g-4s),它在端粒的末端高度表达,在那里它们可以抑制端粒酶的活性,从而稳定g-4s在末端的端粒可以阻碍癌细胞的增殖。四链体在癌症重要基因的启动子中发现和由DNA解旋酶分解,四链体的稳定也可以针对癌症。由于癌细胞通常存在DNA修复途径的缺陷,它们最有可能会受到如聚(ADP-核糖)聚合酶1(PARP-1)和DNA依赖蛋白激酶催化亚基(DNA-PKCS)等综合致死性的影响。
关键词: DNA损伤药物,DNA修复,博来霉素,丝裂霉素C,DNA拓补异构酶1和2抑制剂,DNA结构,致死性
Current Medicinal Chemistry
Title:DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy
Volume: 24 Issue: 15
关键词: DNA损伤药物,DNA修复,博来霉素,丝裂霉素C,DNA拓补异构酶1和2抑制剂,DNA结构,致死性
摘要: DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3’-phosphoglycolate (3’PG) residues repaired by several pathways, but 3’PGs must be processed to the 3’-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells. Although these proteins are essential for nucleotide excision repair (NER), their decreased activity may not be fatal in normal cells as almost all NER substrates can be repaired by other pathways. Four-stranded DNA, resulted mainly from guanine quadruplexes (G-4s), are highly overexpressed at the end of telomeres, where they can inhibit telomerase, hence stabilization G-4s at the telomeres ends can hamper proliferation of cancer cells. Quadruplexes are also found in the promoters of genes important for cancer and are resolved by DNA helicases, which can be targeted in cancer along with stabilization of quadruplexes. As cancer cells often have defects in DNA repair pathway(s), they can be subjected by synthetic lethality, with the most promising results with poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).
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Cite this article as:
DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy, Current Medicinal Chemistry 2017; 24 (15) . https://dx.doi.org/10.2174/0929867324666170124145557
DOI https://dx.doi.org/10.2174/0929867324666170124145557 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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