Division of Pediatrics, Children's Cancer Hospital, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2010 May 15;116(10):2465-75. doi: 10.1002/cncr.25017.
High-risk cases of neuroblastoma have poor survival rates, and novel therapies are needed. Vandetanib (ZD6474, Zactima) is an inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases, which have each been implicated in neuroblastoma pathogenesis. The authors hypothesized that vandetanib combined with 13-cis-retinoic acid (CRA), a differentiating agent used in most current neuroblastoma treatment regimens, would be effective against neuroblastoma tumor models.
The authors evaluated the effects of vandetanib with and without CRA on RET phosphorylation and on the proliferation and survival of human neuroblastoma cell lines in vitro. Using a subcutaneous mouse xenograft model of human neuroblastoma, they analyzed tumors treated with CRA, vandetanib, and the combination of vandetanib plus CRA for growth, gross and histologic appearance, vascularity, and apoptosis.
Vandetanib treatment inhibited RET phosphorylation and resulted in induction of apoptosis in the majority of neuroblastoma cell lines in vitro, whereas CRA treatment induced morphologic differentiation and cell-cycle arrest. Treatment with vandetanib plus CRA resulted in more significant reduction in neuroblastoma cell viability than either alone. In a mouse xenograft model, the combination of vandetanib with CRA demonstrated significantly more growth inhibition than either alone, via both reduction in tumor vascularity and induction of apoptosis.
Vandetanib induces neuroblastoma tumor cell death in vitro and reduces tumor growth and vascularity in vivo. The combination of vandetanib with CRA was more effective in reducing tumor growth than either treatment alone. The antitumor effects of vandetanib plus CRA suggest a novel combination for use in neuroblastoma patients.
高危神经母细胞瘤的存活率较低，需要新的治疗方法。凡德他尼（ZD6474，Zactima）是一种血管内皮生长因子受体、表皮生长因子受体和转染重排（RET）酪氨酸激酶抑制剂，这些受体都与神经母细胞瘤的发病机制有关。作者假设凡德他尼联合 13-顺式维甲酸（CRA），一种目前大多数神经母细胞瘤治疗方案中使用的分化剂，对神经母细胞瘤肿瘤模型有效。
作者评估了凡德他尼联合和不联合 CRA 对 RET 磷酸化以及体外人神经母细胞瘤细胞系增殖和存活的影响。使用人神经母细胞瘤皮下小鼠异种移植模型，分析了 CRA、凡德他尼和凡德他尼联合 CRA 治疗的肿瘤的生长、大体和组织学表现、血管生成和细胞凋亡。
凡德他尼治疗抑制了 RET 磷酸化，并导致大多数神经母细胞瘤细胞系在体外诱导凋亡，而 CRA 治疗诱导了形态分化和细胞周期停滞。凡德他尼联合 CRA 治疗导致神经母细胞瘤细胞活力的显著降低，比单独治疗更为显著。在小鼠异种移植模型中，凡德他尼联合 CRA 治疗通过降低肿瘤血管生成和诱导细胞凋亡，比单独治疗更显著地抑制肿瘤生长。
凡德他尼在体外诱导神经母细胞瘤肿瘤细胞死亡，并在体内减少肿瘤生长和血管生成。凡德他尼联合 CRA 比单独治疗更有效地减少肿瘤生长。凡德他尼联合 CRA 的抗肿瘤作用表明这是一种治疗神经母细胞瘤患者的新的联合治疗方法。
