Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.
Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.
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DOI：
10.1158/1078-0432.ccr-11-0078
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Baruchel S
中科院分区：
文献类型：
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作者：
Kumar S;Mokhtari RB;Sheikh R;Wu B;Zhang L;Xu P;Man S;Oliveira ID;Yeger H;Kerbel RS;Baruchel S
低剂量节律（LDM）化疗联合VEGF信号通路抑制剂是在许多成人临床前癌症模型中协调抑制血管生成和肿瘤生长的高效策略。我们在三种小儿颅外实体瘤小鼠模型中测试了每日口服LDM托泊替康单独给药和与VEGF受体抑制剂帕唑帕尼联合给药的疗效。在几种神经母细胞瘤、骨肉瘤和横纹肌肉瘤细胞系中进行了拓扑替康和帕唑帕尼的体外剂量反应研究。在4种皮下异种移植模型和2种神经母细胞瘤转移模型上测试LDM托泊替康和帕唑帕尼作为单一药剂和组合的体内抗肿瘤功效。循环血管生成因子如循环内皮细胞（CEC）、循环内皮祖细胞（CEP）和微血管密度用作抗血管生成活性的替代生物标志物。在体外，拓扑替康引起所有细胞系活力的剂量依赖性降低，而帕唑帕尼没有。在体内，拓扑替康+帕唑帕尼（TP + PZ）的组合显示出显着的抗肿瘤活性和显着提高生存在所有模型中相比，各自的单一药物。活性CEP和/或CEC水平和肿瘤微血管密度的降低与肿瘤缓解相关，因此证实了方案的抗血管生成活性。两种药物的药代动力学研究均未发现任何药物间相互作用。在儿科肿瘤小鼠模型中，与相应的单药相比，TP + PZ的节拍给药显示出统计学显著的抗肿瘤活性，代表了侵袭性儿科实体瘤维持治疗的有效选择。
Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. In vitro dose–response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug–drug interaction. Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors.