Leblond Pierre, Boulet Elodie, Bal-Mahieu Christine, Pillon Arnaud, Kruczynski Anna, Guilbaud Nicolas, Bailly Christian, Sarrazin Thierry, Lartigau Eric, Lansiaux Amélie, Meignan Samuel
Pediatric oncology unit, Centre Oscar Lambret, Lille, France.
Invest New Drugs. 2014 Oct;32(5):883-92. doi: 10.1007/s10637-014-0132-3. Epub 2014 Jul 11.
The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing radiation and chemotherapeutic agents, was investigated in vitro. The antitumor activity of F14512 was assessed in vivo using a liver-metastatic model of neuroblastoma. An active PTS was evidenced in all tested cell lines, providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Competition experiments confirmed the essential role of PTS in the cell uptake and cytotoxicity of F14512. This cytotoxicity appeared greater in neuroblastoma cells compared with HGG cells but appeared independent of PTS activity levels. In vivo evaluation confirmed a marked and prolonged antitumoral effect in neuroblastoma cells. The combinations of F14512 with cisplatin and carboplatin were often found to be synergistic, and we demonstrated the significant radiosensitizing potential of F14512 in the MYCN-amplified Kelly cell line. Thus, F14512 appears more effective than etoposide in pediatric tumor cell lines, with greater efficacy in neuroblastoma cells compared with HGG cells. The synergistic effects observed with platinum compounds and the radiosensitizing effect could lead to a clinical development of the drug in pediatric oncology.
尽管采用了多学科治疗方法，但高级别胶质瘤（HGG）和高危神经母细胞瘤患儿的预后仍然很差，因此需要针对这些适应症开发新的治疗方法。F14512是一种含有精胺部分的拓扑异构酶II抑制剂，它通过多胺转运系统（PTS）促进肿瘤细胞的选择性摄取，并增加拓扑异构酶II中毒。在此，我们在儿科HGG和神经母细胞瘤细胞系中对F14512进行了评估。使用荧光精胺偶联探针评估PTS活性和特异性。在体外研究了F14512单独或与电离辐射和化疗药物联合使用时的细胞毒性。使用神经母细胞瘤肝转移模型在体内评估F14512的抗肿瘤活性。在所有测试的细胞系中均证实存在活跃的PTS，它能将精胺偶联化合物特异性且快速地转运到细胞核中。竞争实验证实了PTS在F14512的细胞摄取和细胞毒性中起着至关重要的作用。与HGG细胞相比，这种细胞毒性在神经母细胞瘤细胞中似乎更大，但与PTS活性水平无关。体内评估证实F14512对神经母细胞瘤细胞具有显著且持久的抗肿瘤作用。经常发现F14512与顺铂和卡铂联合使用具有协同作用，并且我们证明了F14512在MYCN扩增的凯利细胞系中具有显著的放射增敏潜力。因此，在儿科肿瘤细胞系中，F14512似乎比依托泊苷更有效，与HGG细胞相比，在神经母细胞瘤细胞中疗效更佳。铂类化合物的协同作用和放射增敏作用可能会促使该药物在儿科肿瘤学领域开展临床研究。
