Solecki Gergely, Osswald Matthias, Weber Daniel, Glock Malte, Ratliff Miriam, Müller Hans-Joachim, Krieter Oliver, Kienast Yvonne, Wick Wolfgang, Winkler Frank
Neurology Clinic and Neurooncology Program at the National Center for Tumor Disease, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Cancers (Basel). 2019 Mar 6;11(3):314. doi: 10.3390/cancers11030314.
Antiangiogenic strategies have not shown striking antitumor activities in the majority of glioma patients so far. It is unclear which antiangiogenic combination regimen with standard therapy is most effective. Therefore, we compared anti-VEGF-A, anti-Ang2, and bispecific anti-Ang-2/VEGF-A antibody treatments, alone and in combination with radio- or temozolomide (TMZ) chemotherapy, in a malignant glioma model using multiparameter two-photon in vivo microscopy in mice. We demonstrate that anti-Ang-2/VEGF-A lead to the strongest vascular changes, including vascular normalization, both as monotherapy and when combined with chemotherapy. The latter was accompanied by the most effective chemotherapy-induced death of cancer cells and diminished tumor growth. This was most probably due to a better tumor distribution of the drug, decreased tumor cell motility, and decreased formation of resistance-associated tumor microtubes. Remarkably, all these parameters where reverted when radiotherapy was chosen as combination partner for anti-Ang-2/VEGF-A. In contrast, the best combination partner for radiotherapy was anti-VEGF-A. In conclusion, while TMZ chemotherapy benefits most from combination with anti-Ang-2/VEGF-A, radiotherapy does from anti-VEGF-A. The findings imply that uninformed combination regimens of antiangiogenic and cytotoxic therapies should be avoided.
到目前为止，抗血管生成策略在大多数胶质瘤患者中尚未显示出显著的抗肿瘤活性。目前尚不清楚哪种抗血管生成联合方案与标准治疗联合最为有效。因此，我们在小鼠恶性胶质瘤模型中，使用多参数双光子体内显微镜，比较了抗VEGF-A、抗Ang2和双特异性抗Ang-2/VEGF-A抗体单独治疗以及与放疗或替莫唑胺（TMZ）化疗联合治疗的效果。我们证明，抗Ang-2/VEGF-A无论是作为单一疗法还是与化疗联合使用，都会导致最强烈的血管变化，包括血管正常化。后者伴随着化疗诱导的最有效的癌细胞死亡和肿瘤生长的减缓。这很可能是由于药物在肿瘤中的分布更好、肿瘤细胞运动性降低以及与耐药相关的肿瘤微管形成减少。值得注意的是，当选择放疗作为抗Ang-2/VEGF-A的联合伙伴时，所有这些参数都发生了逆转。相比之下，放疗的最佳联合伙伴是抗VEGF-A。总之，虽然TMZ化疗与抗Ang-2/VEGF-A联合获益最大，但放疗与抗VEGF-A联合获益最大。这些发现意味着应避免盲目使用抗血管生成和细胞毒性疗法的联合方案。
