Vasoactivity of AG014699, a Clinically Active Small Molecule Inhibitor of Poly(ADP-ribose) Polymerase: a Contributory Factor to Chemopotentiation In vivo?
Vasoactivity of AG014699, a Clinically Active Small Molecule Inhibitor of Poly(ADP-ribose) Polymerase: a Contributory Factor to Chemopotentiation In vivo?
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DOI：
10.1158/1078-0432.ccr-09-0398
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发表时间：
2009-10-01
影响因子：
11.5
通讯作者：
Williams, Kaye J.
中科院分区：
文献类型：
--
作者：
Ali, Majid;Telfer, Brian A.;Williams, Kaye J.
目的：聚ADP核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）在DNA修复中起重要作用，PARP抑制剂可增强DNA损伤剂的体内外活性。AG 014699是一种有效的PARP抑制剂，处于II期临床开发阶段。然而，AG 014699可以通过基于DNA修复的机制与之相互作用的治疗剂的范围是有限的。我们的目的是研究一种新的，血管为基础的活性AG 014699，潜在的体内化疗增敏，这可能会扩大其临床应用。实验设计：替莫唑胺反应进行了分析，在体外和体内。在灌注标记物给药后使用“失配”监测血管动力学，并实时分析背窗室中建立的肿瘤中荧光标记的白蛋白摄取。进一步的机制研究使用离体血管平滑肌松弛，肠道运动，和肌球蛋白轻链激酶（MLCK）inhibit 1 n.Results：AG 014699未能敏感SW 620细胞替莫唑胺在体外，但在体内诱导显着增强。AG 014699（lmg/kg）改善了肿瘤灌注，与对照剂烟酰胺（lg/kg）和AG 14361（AG 014699的前身; 10 mg/kg）相比。AG 014699和AG 14361比标准药物肼苯哒嗪更有效地松弛预收缩的血管平滑肌，对肠道运动没有影响。AG 014699在使离体动脉松弛的浓度下抑制MLCK，而AG 14361则无作用。结论：AG 014699引起的血管灌注增加可增加肿瘤药物蓄积和治疗反应。血管活性浓度的AG 014699不会对肠道蠕动造成有害的副作用，并且可能增加AG 014699可以与之组合以获得临床益处的治疗范围。(Clin Cancer Res 2009;15（19）：6106-12）
Purpose: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application.Experimental Design: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition.Results: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect.Conclusion: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit. (Clin Cancer Res 2009;15(19):6106-12)