PARP Inhibitors Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer
PARP Inhibitors Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer
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DOI：
10.2165/11635510-000000000-00000
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发表时间：
2012-01-01
期刊：
影响因子：
11.5
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
--
作者：
Basu, Bristi;Sandhu, Shahneen K.;de Bono, Johann S.
聚（ADP-核糖）聚合酶（PARP）抑制剂的使用为合成致命抗癌策略提供了概念验证，因为它们在 BRCA1/2 突变携带者中具有功效和良好的毒性特征。目前正在努力确定更广泛的具有基因组易感性的患者群体，这些患者可能会受益于这些药物。为了增强抗肿瘤效果，PARP抑制剂已与传统的细胞毒疗法和放射疗法相结合；然而，优化这些联合治疗方案的给药方案仍然是最大化益处同时减轻毒性增加的可能性的关键。随着 PARP 抑制的临床经验的不断积累，对这些疗法的耐药机制正在被阐明，并且需要解决长期服用这些药物的具体挑战。如果要充分发挥这些药物的潜力，就必须开发稳健的反应预测生物标志物，以实现最佳患者选择和合理的组合策略。
The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anti-cancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.