Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, Texas.
RTI, Research Triangle Park, North Carolina.
Clin Cancer Res. 2020 Jun 15;26(12):3012-3023. doi: 10.1158/1078-0432.CCR-19-1822. Epub 2020 Mar 17.
Vincristine combined with camptothecin derivatives showed synergy in preclinical pediatric cancer models, and the combinations are effective in treatment of childhood solid tumors. We determined whether the synergy between vincristine and irinotecan extends to eribulin, another microtubule inhibitor.
Vincristine or eribulin, alone or combined with irinotecan, was studied in 12 xenograft models. Tumor regression and time to event were used to assess antitumor activity. Pharmacodynamic studies and RNA sequencing (RNA-seq) were conducted 24 and 144 hours after single-agent or combination treatment. Effects on vascular development were studied in Matrigel plugs implanted in mice. The interaction between binary combinations was examined .
Eribulin combined with irinotecan was more effective than vincristine-irinotecan in 6 of 12 models. Pharmacodynamic markers induced by eribulin (phospho-histone H3) and irinotecan (γ-H2A.X) were abrogated in combination-treated tumors. The predominant RNA-seq signature in combination-treated tumors was activation of the TP53 pathway with increased nuclear TP53. Massive apoptosis was observed 24 hours only after treatment with the eribulin combination. , neither combination showed interaction using combination index analysis. Eribulin alone and the combination caused alterations in developing vasculature.
The eribulin combination is very active in these xenograft models, but not synergistic . The combination reduced pharmacodynamic markers indicative of single-agent mechanisms but in tumors, dramatically activated the TP53 pathway. Although a mechanism for synergy requires further study, it is possible that eribulin-induced inhibition of microtubule dynamics enhances irinotecan-induced nuclear accumulation of TP53, leading to rapid cell death.
长春新碱与喜树碱衍生物联合应用在儿科癌症模型中具有协同作用，且这些联合用药对儿童实体瘤的治疗有效。我们确定长春新碱与伊立替康之间的协同作用是否扩展到另一种微管抑制剂埃博霉素。
单独或联合应用长春新碱或埃博霉素，联合或不联合伊立替康，对 12 种异种移植模型进行研究。采用肿瘤消退和时间事件评估抗肿瘤活性。在单药或联合治疗后 24 小时和 144 小时进行药效学研究和 RNA 测序（RNA-seq）。在植入小鼠的 Matrigel 塞中研究血管发育的影响。检查二元组合的相互作用。
在 12 种模型中的 6 种模型中，埃博霉素联合伊立替康比长春新碱-伊立替康更有效。埃博霉素（磷酸组蛋白 H3）和伊立替康（γ-H2A.X）诱导的药效学标志物在联合治疗的肿瘤中被阻断。联合治疗的肿瘤中主要的 RNA-seq 特征是 TP53 通路的激活，核内 TP53 增加。仅在用埃博霉素联合治疗后 24 小时观察到大量细胞凋亡。组合指数分析表明，两种组合均无相互作用。单独使用埃博霉素和联合用药都会导致发育中的血管发生改变。
埃博霉素联合在这些异种移植模型中非常活跃，但没有协同作用。该联合用药减少了单一药物机制的药效学标志物，但在肿瘤中，显著激活了 TP53 通路。尽管协同作用的机制需要进一步研究，但埃博霉素诱导的微管动力学抑制可能增强伊立替康诱导的 TP53 核内积累，从而导致快速细胞死亡。
