摘要
维持基因组稳定性是细胞存活的关键决定因素,也是恶性细胞生长和发育所必需的条件。股间交联(ICL)的活性剂,包括铂类药物,是许多人类癌症化疗一线治疗用药。在恶性细胞里,ICL触发DNA损伤反应(DDR),当损伤负担高且损伤无法修复时,恶性细胞无法分裂,最终通过细胞分裂突变或凋亡而死亡。ICL的活性剂,特别是铂类为基础的治疗方法,建立“分子景观”,即一种可以DNA损伤模式可能进一步利用DDR的靶向药物治疗。如果在分子水平上更好地定义了基于铂的药物所创造的分子景观,就可以开发出一套系统的、机械的原理,用于在临床上用特定的联合/维持方案使用DDR靶向治疗晚期恶性肿瘤。新的治疗药物如多聚(ADP-核糖)聚合酶(PARP)抑制剂就是DDR的靶向治疗的一个例子,它可以增加DNA损伤和铂类药物在肿瘤细胞中的复制应激以及为晚期恶性肿瘤患者提供治疗益处。最近的研究表明, PARP抑制剂与铂类药物的联合使用是一种很有前途的治疗有“BRCAness”基因表型的卵巢癌患者的治疗策略,例如,肿瘤的表型特征不仅可以参与或者BRCA1或BRCA2基因失去功能的突变,而且也参与包括BRCA突变的肿瘤的分子特征。基于这些有希望的结果,应考虑对铂类药物与各种DDR靶向治疗相结合的机制研究。本文综述了,总的来说,(1)ICL活性剂,主要是铂类药物,建立了分子景观,可以进一步开发用于治疗;(2)ICL活性剂诱导交联后,进一步导致细胞死亡,使用DDR靶向药物联合或维持治疗;(3)可考虑在临床上用铂类药物联合/维持治疗晚期恶性肿瘤患者。
关键词: 铂类药物,DDR的靶向药物,DNA修复酶,WEE-1
Current Medicinal Chemistry
Title:Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions
Volume: 24 Issue: 15
关键词: 铂类药物,DDR的靶向药物,DNA修复酶,WEE-1
摘要: Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a “molecular landscape,” i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with ”BRCAness”, i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent–induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.
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Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions, Current Medicinal Chemistry 2017; 24 (15) . https://dx.doi.org/10.2174/0929867323666161214114948
DOI https://dx.doi.org/10.2174/0929867323666161214114948 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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