Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.
Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.
复制标题
在非小细胞肺癌异种移植物和人类中延长亲脂性喜树碱类似物 AR-67 的给药。
DOI：
10.1007/s00280-014-2472-2
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发表时间：
2014
影响因子：
3
通讯作者：
Leggas,Markos
中科院分区：
文献类型：
--
作者：
Tsakalozou,Eleftheria;Adane,EyobD;Liang,Yali;Arnold,SusanneM;Leggas,Markos
目的虽然喜树碱抗肿瘤作用的临床前研究已经证明了低剂量延长给药的优越性，但这些发现在临床上并不重复。7-叔丁基二甲基甲硅烷基-10-羟基喜树碱（AR-67）是一种喜树碱类似物，目前正在早期临床试验中进行研究。为了最大限度地发挥AR-67的治疗潜力，我们试图找出影响反应treatment.MethodsAfter确定的最大耐受剂量使用中性粒细胞减少症作为毒性终点的因素，异种移植物接受AR-67根据不同的给药方案，并监测生存。在治疗的最后一天，收集肿瘤组织并评估拓扑异构酶1（Top1）、γ H2 AX、半胱天冬酶3和PARP蛋白含量。AR-67血浆和肿瘤的药代动力学也进行了研究，在小鼠和癌症患者谁被管理AR-67作为1小时静脉输注的第1天，第4天，第8天，第12天和第15天，每21 days.ResultsLow-dose延长给药时间表增加动物的生存率相比，频率较低，但高剂量的课程和Top1和γ H2 AX的表达时间表依赖。疲劳和中性粒细胞减少症是在接受AR-67的患者中确定的剂量限制性毒性。最后，AR-67从肿瘤部位的消除是缓慢的异种移植物和肿瘤的患者参加了试点clinical trial.ConclusionsWe表明，低剂量的长期给药方案的AR-67是治疗有效的和Top1反映了AR-67在异种移植物的生物活性。此外，肿瘤药代动力学以及间歇给予癌症患者AR-67的疗效和安全性需要进一步研究。
PurposeAlthough preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment.MethodsAfter determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days.ResultsLow-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial.ConclusionsWe demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.