Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Room 323, Lexington, KY, 40536, USA.
Cancer Chemother Pharmacol. 2014 Jul;74(1):45-54. doi: 10.1007/s00280-014-2472-2. Epub 2014 May 8.
Although 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.
After 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.
Low-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.
We 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.
尽管临床前研究表明，低剂量持续给药方案在抗肿瘤方面具有优势，但这些发现并未在临床中得到证实。7-t-丁基二甲基硅基-10-羟基喜树碱（AR-67）是一种喜树碱类似物，目前正在进行早期临床试验。为了最大限度地发挥 AR-67 的治疗潜力，我们试图确定影响治疗反应的因素。
使用中性粒细胞减少症作为毒性终点确定最大耐受剂量后，根据不同的给药方案给异种移植物施用 AR-67，并监测其存活情况。在最后一次治疗日，收集肿瘤组织，并评估拓扑异构酶 1（Top1）、γH2AX、半胱氨酸天冬氨酸蛋白酶 3 和多聚（ADP-核糖）聚合酶（PARP）的蛋白含量。还在接受 AR-67 治疗的小鼠和癌症患者中研究了 AR-67 的血浆和肿瘤药代动力学，患者接受 AR-67 治疗方案为：第 1、4、8、12 和 15 天，每 21 天静脉输注 1 小时，剂量为 1 小时。
与频率较低但剂量较高的方案相比，低剂量持续给药方案可提高动物的存活率，并且 Top1 和 γH2AX 的表达与方案有关。在接受 AR-67 治疗的患者中，疲劳和中性粒细胞减少症是确定的剂量限制毒性。最后，在异种移植物和参加初步临床试验的患者的肿瘤中，AR-67 从肿瘤部位的消除速度较慢。
我们证明了 AR-67 的低剂量持续给药方案具有治疗效果，并且 Top1 反映了 AR-67 在异种移植物中的生物学活性。此外，AR-67 间歇性给予癌症患者的肿瘤药代动力学以及疗效和安全性值得进一步研究。
