Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City, NY 10065, USA.
Cancer J. 2010 Jan-Feb;16(1):48-52. doi: 10.1097/PPO.0b013e3181cf01eb.
Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.
聚（ADP-核糖）聚合酶（PARPs）参与细胞对各种形式损伤的多种反应。PARP-1 和 PARP-2 是最丰富的 PARPs，它们是对特定类型 DNA 损伤（尤其是单链断裂）反应的核心。PARP 活性的抑制可能使细胞对化疗和辐射等外源性药物敏感。在补救途径不足的情况下，特别是同源重组（HR）定向 DNA 修复途径，PARP 的抑制可能导致“合成致死”。BRCA 突变相关的乳腺癌是 HR 定向修复缺陷肿瘤的范例。早期临床试验表明，单 PARP 抑制剂在 BRCA 缺陷型乳腺癌和卵巢癌中具有显著活性。由于一些“三阴性”乳腺癌（TNBC）与 BRCA1 突变携带者中最常见的乳腺癌类型之间存在表型相似性，因此有人假设 TNBC 可能也对 PARP 抑制特别敏感。尚未报道 TNBC 中单一 PARP 抑制剂的活性。一项试验确实表明，铂类联合化疗的活性显著增强，而没有增加毒性。这些研究表明，PARP 抑制是治疗携带 BRCA 突变的女性乳腺癌和可能具有 HR 定向修复缺陷的散发性癌症的一种令人兴奋的新方法。未来的研究将有必要确定 PARP 抑制剂在非遗传性癌症中的有效性是否需要潜在的 HR 缺陷，或者这些药物是否可以通过其他方式提高常规化疗的活性。此外，还需要研究 PARP 抑制剂是否会在 BRCA 依赖性 DNA 修复途径以外的其他途径存在缺陷的肿瘤中诱导合成致死。如果这两种情况中的任何一种或两种情况都是如此，那么 PARP 抑制可能会使广泛的癌症患者受益。
