Reppingen Norman, Helm Alexander, Doleschal Laura, Durante Marco, Fournier Claudia
Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Darmstadt, Germany.
Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.
Front Oncol. 2021 Dec 8;11:788182. doi: 10.3389/fonc.2021.788182. eCollection 2021.
The tyrosine kinase inhibitor Cabozantinib has been applied in clinical studies in combination with radiotherapy. We investigated the effect of such combination on triple-negative 4T1 cells as a metastatic breast cancer model and upon inoculation in BALB/c mice. assays indicated a potential for improved effects using the combination. Both Cabozantinib (2.5 µM) and 10 Gy of 250 kV x-rays were able to cease the growth of 4T1 cells as revealed by growth curves. In a clonogenic survival assay, the effect of Cabozantinib added on the effects of irradiation and the effectiveness of inhibiting the clonogenic survival was found to be 2 (RBE). Additionally, cell death measurements of apoptosis plus necrosis revealed a synergistic effect when combining irradiation with Cabozantinib. Surprisingly, however, tumor growth kinetics showed no additional effect in growth control when irradiation was used together with Cabozantinib. Since both ionizing radiation and Cabozantinib are acknowledged to feature immunogenic effects, we additionally investigated the effect of the treatments on lung metastases. No difference to the control groups was found here, neither for irradiation nor Cabozantinib alone nor in combination. Yet, upon analysis of the mice' livers, CD11b-positive cells, indicating immune suppressive myeloid derived suppressor cells were found diminished following treatment with Cabozantinib. In conclusion, despite promising controls of the combination of Cabozantinib and irradiation, tumor growth control was not increased by the combination, which was true also for the occurrence of lung metastases.
酪氨酸激酶抑制剂卡博替尼已应用于与放疗联合的临床研究中。我们研究了这种联合用药对作为转移性乳腺癌模型的三阴性4T1细胞以及接种于BALB/c小鼠后的影响。实验表明联合用药有提高疗效的潜力。生长曲线显示，卡博替尼（2.5 µM）和250 kV X射线10 Gy均能抑制4T1细胞的生长。在克隆形成存活实验中，发现添加卡博替尼对辐射效果及抑制克隆形成存活的有效性的影响为2（相对生物效应）。此外，细胞凋亡加坏死的细胞死亡测量结果显示，辐射与卡博替尼联合使用时有协同效应。然而，令人惊讶的是，肿瘤生长动力学显示，卡博替尼与辐射联合使用时，在生长控制方面没有额外效果。由于电离辐射和卡博替尼都被认为具有免疫原性效应，我们还研究了这些治疗对肺转移的影响。在此，无论是单独放疗、单独使用卡博替尼还是联合使用，与对照组相比均未发现差异。然而，在对小鼠肝脏进行分析时，发现用卡博替尼治疗后，表明免疫抑制性髓源性抑制细胞的CD11b阳性细胞数量减少。总之，尽管卡博替尼与放疗联合使用有良好的控制效果，但联合使用并未增加肿瘤生长控制效果，对肺转移的发生情况也是如此。
