A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.
A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.
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DOI：
10.1038/bjc.2011.8
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发表时间：
2011-03-01
影响因子：
8.8
通讯作者：
Middleton, M. R.
中科院分区：
文献类型：
--
作者：
Khan, O. A.;Gore, M.;Lorigan, P.;Stone, J.;Greystoke, A.;Burke, W.;Carmichael, J.;Watson, A. J.;McGown, G.;Thorncroft, M.;Margison, G. P.;Califano, R.;Larkin, J.;Wellman, S.;Middleton, M. R.
多聚腺苷二磷酸（ADP）-核糖聚合酶（PARP）通过碱基切除修复途径（BER）在DNA损伤的细胞加工中是必不可少的。PARP抑制可对肿瘤细胞具有直接细胞毒性，并增强DNA损伤剂的抗肿瘤作用。本研究评价了奥拉帕尼（4-（3--4-氟苯基）甲基-1（2 H）-酮; AZD 2281，KU 0059436）（一种强效PARP抑制剂）与达卡巴嗪的最佳耐受剂量，并评估了联合治疗的安全性、毒性、临床药代动力学和疗效。晚期癌症患者在21天周期的第1-7天接受奥拉帕尼（20-200 mg PO），第1天（第2周期，第2天）接受达卡巴嗪（600-800 mg m−2 IV）。以最佳耐受剂量治疗未经化疗的黑色素瘤患者的扩展队列。BER酶，甲基嘌呤-DNA糖基化酶和其底物7-甲基鸟嘌呤在外周血单个核细胞中进行定量。进入II期的最佳组合定义为100 mg bd olaparib +600 mg m−2达卡巴嗪。剂量限制性毒性为血小板减少和血小板减少。有2例部分缓解，均发生在黑色素瘤患者中。该研究确定了奥拉帕尼联合达卡巴嗪的耐受剂量，但在化疗未接受的黑色素瘤患者中没有反应，表明在这些剂量下与达卡巴嗪单药相比没有临床优势。
Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. Patients with advanced cancer received olaparib (20–200 mg PO) on days 1–7 with dacarbazine (600–800 mg m−2 IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m−2 dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.
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影响因子：
3
作者：
Tentori, L;Portarena, I;Graziani, G
通讯作者：
Graziani, G
影响因子：
8.8
作者：
Watson, A. J.;Middleton, M. R.;McGown, G.;Thorncroft, M.;Ranson, M.;Hersey, P.;McArthur, G.;Davis, I. D.;Thomson, D.;Beith, J.;Haydon, A.;Kefford, R.;Lorigan, P.;Mortimer, P.;Sabharwal, A.;Hayward, O.;Margison, G. P.
通讯作者：
Margison, G. P.
影响因子：
7.3
作者：
Menear, Keith A.;Adcock, Claire;Martin, Niall M. B.
通讯作者：
Martin, Niall M. B.
影响因子：
11.4
作者：
Tentori, L;Turriziani, M;Graziani, G
通讯作者：
Graziani, G
DOI：
10.1158/1078-0432.ccr-08-1223
发表时间：
2008-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Plummer R;Jones C;Middleton M;Wilson R;Evans J;Olsen A;Curtin N;Boddy A;McHugh P;Newell D;Harris A;Johnson P;Steinfeldt H;Dewji R;Wang D;Robson L;Calvert H
通讯作者：
Calvert H