Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.
Tumour cell retention of rucaparib, sustained PARP inhibition and efficacy of weekly as well as daily schedules.
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DOI：
10.1038/bjc.2014.91
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发表时间：
2014-04-15
影响因子：
8.8
通讯作者：
Curtin, N. J.
中科院分区：
文献类型：
--
作者：
Murray, J.;Thomas, H.;Berry, P.;Kyle, S.;Patterson, M.;Jones, C.;Los, G.;Hostomsky, Z.;Plummer, E. R.;Boddy, A. V.;Curtin, N. J.
聚（ADP-核糖）聚合酶-1（PARP）抑制剂（PARPi）利用同源重组DNA修复中的肿瘤特异性缺陷，连续给药最有效。rucaparib的早期临床试验数据表明，它可引起持续的PARP抑制。在这里，我们探讨这种持久的抑制和潜在的开发机制。在人癌细胞系中，通过放射化学和免疫学试验测定rucaparib的摄取和保留以及PARP抑制的持续性。在荷瘤小鼠中测定rucaparib的药代动力学和药效学，并在荷同源重组DNA修复缺陷型肿瘤的小鼠中测定rucaparib不同给药方案的疗效。Rucaparib蓄积是载体介导的（Km=8.4±1.2 μM，Vmax=469±22 pmol/106个细胞/10 min），在30 min内达到稳态水平，比细胞外浓度高10倍以上。Rucaparib保留在细胞中，并在400 nM脉冲30分钟后抑制PARP 50%达72小时。在Capan-1荷瘤小鼠中，rucaparib蓄积并保留在肿瘤中，在10 mg kg−1 i.p或150 mg kg−1 p.o.单次给药后，PARP被抑制7天。70%和90%。每周一次口服150 mg kg−1与每周5天每天i. p. 10 mg kg−1持续6周在延迟Capan-1肿瘤生长方面同样有效。Rucaparib蓄积并保留在肿瘤细胞中，并长时间抑制PARP，因此在临床前模型中每周给药方案与每日给药方案具有等同的抗癌活性，这表明应考虑对Rucaparib替代方案进行临床评价。
Poly(ADP-ribose) polymerase-1 (PARP) inhibitors (PARPi) exploit tumour-specific defects in homologous recombination DNA repair and continuous dosing is most efficacious. Early clinical trial data with rucaparib suggested that it caused sustained PARP inhibition. Here we investigate the mechanism of this durable inhibition and potential exploitation. Uptake and retention of rucaparib and persistence of PARP inhibition were determined by radiochemical and immunological assays in human cancer cell lines. The pharmacokinetics and pharmacodynamics of rucaparib were determined in tumour-bearing mice and the efficacy of different schedules of rucaparib was determined in mice bearing homologous recombination DNA repair-defective tumours. Rucaparib accumulation is carrier mediated (Km=8.4±1.2 μM, Vmax=469±22 pmol per 106 cells per 10 min), reaching steady-state levels >10 times higher than the extracellular concentration within 30 min. Rucaparib is retained in cells and inhibits PARP ⩾50% for ⩾72 h days after a 30-min pulse of 400 nM. In Capan-1 tumour-bearing mice rucaparib accumulated and was retained in the tumours, and PARP was inhibited for 7 days following a single dose of 10 mg kg−1 i.p or 150 mg kg−1 p.o. by 70% and 90%, respectively. Weekly dosing of 150 mg kg−1 p.o once a week was as effective as 10 mg kg−1 i.p daily for five days every week for 6 weeks in delaying Capan-1 tumour growth. Rucaparib accumulates and is retained in tumour cells and inhibits PARP for long periods such that weekly schedules have equivalent anticancer activity to daily dosing in a pre-clinical model, suggesting that clinical evaluation of alternative schedules of rucaparib should be considered.
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影响因子：
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作者：
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