The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.
The clinically active PARP inhibitor AG014699 ameliorates cardiotoxicity but does not enhance the efficacy of doxorubicin, despite improving tumor perfusion and radiation response in mice.
复制标题
DOI：
10.1158/1535-7163.mct-11-0356
复制
发表时间：
2011-12
影响因子：
5.7
通讯作者：
Williams KJ
中科院分区：
文献类型：
--
作者：
Ali M;Kamjoo M;Thomas HD;Kyle S;Pavlovska I;Babur M;Telfer BA;Curtin NJ;Williams KJ
AG 014699是第一个进入癌症患者临床试验的DNA修复酶聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂。除了增强DNA损伤化疗的细胞毒性作用外，我们先前已经表明AG 014699具有血管活性，从而具有改善药物生物分布的潜力。临床药物多柔比星的有效性受到肿瘤渗透性差和通过PARP过度激活引起的心脏毒性的混淆。在此，我们分析了AG 014699对乳腺（MDA-MB-231）和结肠直肠（SW 620，LoVo）肿瘤模型中阿霉素耐受性和反应的影响。正如预期的那样，AG 014699在体外并未增强对阿霉素的反应。在体内，AG 014699不影响阿霉素的药代动力学，但改善心脏毒性。与雌性小鼠相比，雄性小鼠的毒性和改善程度更明显。AG 014699改善了MDA-MB-231和SW 620肿瘤中的血管灌注，但这并没有导致多柔比星的肿瘤积累改善，也没有增强治疗反应。相比之下，当与放射治疗组合时，AG 014699在体外和体内均显著增强反应。肿瘤血管功能的实时评估和伴随的组织学研究表明，多柔比星引起了深刻的抗血管效应，抵消了AG 014699对灌注的积极作用。这些数据表明，尽管AG 014699可以通过改善递送来增强对一些化疗的反应，但这不适用于多柔比星。PARP抑制剂仍然可以用于对抗阿霉素毒性，如果性别效应从啮齿动物转化为人类，这将对男性产生更大的影响。
AG014699 was the first inhibitor of the DNA-repair enzyme Poly(ADP-ribose) polymerase-1 (PARP-1) to enter clinical trial in cancer patients. In addition to enhancing the cytotoxic effect of DNA-damaging chemotherapies, we have previously shown that AG014699 is vasoactive, thereby having the potential to improve drug biodistribution. The effectiveness of the clinical agent doxorubicin is confounded both by poor tumour penetration and cardiotoxicity elicited via PARP hyperactivation. Here we analysed the impact of AG014699 on doxorubicin tolerance and response in breast (MDA-MB-231) and colorectal (SW620, LoVo) tumour models in vitro and in vivo. As anticipated, AG014699 did not potentiate response to doxorubicin in vitro. In vivo, AG014699 did not influence the pharmacokinetics of doxorubicin, but did ameliorate cardiotoxicity. Both toxicity and extent of amelioration were more pronounced in male versus female mice. AG014699 improved vessel perfusion in both MDA-MB-231 and SW620 tumours yet this did not lead to improved tumour-accumulation of doxorubicin nor enhanced therapeutic response. In contrast, when combined with radiotherapy, AG014699 significantly enhanced response both in vitro and in vivo. Real-time assessment of tumour vessel function and companion histological studies suggest that doxorubicin causes a profound anti-vascular effect that countered the positive effect of AG014699 on perfusion. These data suggest that although AG014699 can enhance response to some chemotherapies via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity and if the gender effect translates from rodents to humans, this would have greater effect in males.