Department of Medicine, Clinical Genetics and Breast Cancer Medicine Services, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Oncology (Williston Park). 2010 Jan;24(1):55-62.
As knowledge increases about the processes underlying cancer, it is becoming feasible to design "targeted therapies" directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through "synthetic lethality" if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in "triple-negative" breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.
随着对癌症相关过程的认识不断增加，设计针对特定通路的“靶向治疗”成为可能，这些通路对恶性表型的发生或维持至关重要。聚（ADP-核糖）聚合酶（PARP）抑制剂就是这种新方法的一个例子。DNA 损伤修复是一个复杂且多方面的过程，对细胞存活至关重要。PARP 家族成员是特定 DNA 损伤修复途径的核心，特别是碱基切除修复（BER）途径。PARP 抑制会随后损害 BER 机制，可能会增强产生 DNA 单链断裂的药物（如辐射和某些化疗药物）的细胞毒性。此外，如果拯救 BER 缺陷细胞的 DNA 修复机制本身受到损害，PARP 抑制剂可能会通过“合成致死性”诱导细胞死亡。据认为，这种机制是 PARP 抑制在 BRCA 相关乳腺癌和卵巢癌中产生显著疗效的基础，也可能解释了这种方法在“三阴性”乳腺癌中报告的益处。本文将探讨 PARP 抑制作为乳腺癌治疗方法的现有认识、正在进行的临床试验以及这种新方法的未来方向。
