Daniel Rachel A, Rozanska Agata L, Thomas Huw D, Mulligan Evan A, Drew Yvette, Castelbuono Deborah J, Hostomsky Zdenek, Plummer E Ruth, Boddy Alan V, Tweddle Deborah A, Curtin Nicola J, Clifford Steven C
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
Clin Cancer Res. 2009 Feb 15;15(4):1241-9. doi: 10.1158/1078-0432.CCR-08-1095. Epub 2009 Jan 27.
High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers.
We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices.
Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (Cmax, 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (Cmax, 1-2 micromol/L at 120 min), associated with a sustained suppression of PARP-1 enzyme activity. Doses of AG014699 required for potentiation were not toxic per se.
These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.
高危神经母细胞瘤的特点是生存率低，因此开发改进的治疗方法是当务之急。替莫唑胺和拓扑替康对神经母细胞瘤显示出有前景的临床活性。聚（ADP-核糖）聚合酶-1（PARP-1）在基因毒性损伤后促进DNA修复和细胞存活；我们推测抑制它可能增强这些DNA损伤药物在儿童癌症中的疗效。
我们评估了PARP抑制剂AG014699（辉瑞公司）与替莫唑胺和拓扑替康联合使用对人神经母细胞瘤细胞和异种移植瘤的化学增敏特性，以及相关的药理学和毒理学指标。
添加PARP抑制浓度的AG014699在体外显著增强了拓扑替康（1.5至2.3倍）和替莫唑胺（3至10倍）的生长抑制作用，克隆形成试验证实了类似效果。在两个独立的体内模型（NB1691和SHSY5Y异种移植瘤）中，替莫唑胺导致异种移植瘤生长延迟，联合使用AG014699可增强这种延迟，并在大多数（10例中的6例；60%）病例中导致肿瘤完全且持续消退。在NB1691异种移植瘤中观察到拓扑替康/AG014699联合给药增强生长延迟的证据。AG014699代谢产物迅速分布到血浆中（30分钟时Cmax为1.2至1.9 nmol/L）并在异种移植瘤组织中积累（120分钟时Cmax为1至2 μmol/L），与PARP-1酶活性的持续抑制相关。增强作用所需的AG014699剂量本身并无毒性。
这些数据表明PARP抑制可增强替莫唑胺和拓扑替康在神经母细胞瘤中的疗效。结合AG014699可接受的药代动力学、药效学和毒性特征，我们的发现为在儿童早期临床研究中研究PARP抑制剂提供了有力的理论依据。
