namitecan(ST1968)在小儿肉瘤临床前模型中的疗效与抗血管生成作用有关。

PubMed ID
发表日期 2012年Jul月

原始出处 生化药理学
Biochemical pharmacology
作者 Cassinelli  Giuliana  Zuco  Valentina  Petrangolini  Giovanna  De Cesare  Michelandrea  Tortoreto  Monica  Lanzi  Cinzia  Cominetti  Denis  Zaffaroni  Nadia  Orlandi  Augusto  Passeri  Daniela  Meco  Daniela  Di Francesco  Angela Maria  Riccardi  Riccardo  Bucci  Federica  Pisano  Claudio  Zunino  Franco 

文献标题 namitecan(ST1968)在小儿肉瘤临床前模型中的疗效与抗血管生成作用有关。
The curative efficacy of namitecan (ST1968) in preclinical models of pediatric sarcoma is associated with antiangiogenic effects.

文献摘要

Namitecan(ST1968)是一种新型的亲水性喜树碱类似物,7-氧亚氨基甲基系列,被选为临床开发的基础上,其有希望的临床前疗效。鉴于喜树碱对儿童肿瘤的疗效已有临床证据,本研究旨在探讨喜树碱衍生物在儿童肉瘤模型中的抗肿瘤和抗血管生成活性。除了未分化的横纹肌肉瘤(A204),在一个由五个模型组成的小组中,即使在耐受性良好的次优剂量下,纳米比亚也显示出疗效。namitecan良好的治疗指标可能反映了肿瘤部位高而持久的药物积聚。4例反应性肿瘤均表现为高拓扑异构酶I表达。在RD/TE-671横纹肌肉瘤模型中,药物活性与明显的抗血管生成作用有关,这与VEGF、bFGF、多功能趋化因子CCL-2和CXCL16等促血管生成因子的下调一致。与这种调节一致,低剂量的纳米特康与其他抗血管生成药物,如贝伐单抗(人源化抗血管内皮生长因子抗体)和舒尼替尼(多靶点酪氨酸激酶抑制剂,有效对抗与血管生成过程有关的受体)结合,增强了抗肿瘤作用。总之,这项临床前研究提供了纳米特康在良好耐受剂量下对儿童肉瘤模型疗效的证据,可能反映了抗血管生成作用的贡献。基于有希望的治疗概况,namitecan是一个很好的候选临床评估小儿肉瘤。


Namitecan (ST1968), a novel hydrophilic camptothecin analog of the 7-oxyiminomethyl series, was selected for clinical development on the basis of its promising preclinical efficacy. Since there is clinical evidence of efficacy of camptothecins against pediatric tumors, this study was performed to explore the antitumor and antiangiogenic activity of the camptothecin derivative in pediatric sarcoma models. With the exception of an undifferentiated rhabdomyosarcoma (A204), namitecan exhibited curative efficacy even at well-tolerated suboptimal doses in a panel of five models. The good therapeutic index of namitecan likely reflected a high and persistent drug accumulation at tumor site. The four responsive tumors were characterized by high topoisomerase I expression. In the RD/TE-671 rhabdomyosarcoma model the drug activity was associated with a marked antiangiogenic effect, which was consistent with the downregulation of proangiogenic factors, including VEGF, bFGF and the multifunctional chemokines CCL-2 and CXCL16. In agreement with this modulation, the combination of low doses of namitecan with other antiangiogenic agents, such as bevacizumab (a humanized anti-VEGF antibody) and sunitinib (a multitarget tyrosine kinase inhibitor effective against receptors implicated in the angiogenesis process), enhanced the antitumor effects. In conclusion, this preclinical study provides evidence of curative efficacy of namitecan at well-tolerated doses against pediatric sarcoma models, likely reflecting a contribution of antiangiogenic effects. Based on the promising therapeutic profile, namitecan is a good candidate for clinical evaluation in pediatric sarcomas.


获取全文 10.1016/j.bcp.2012.04.005