Huber Peter E, Bischof Marc, Jenne Jürgen, Heiland Sabine, Peschke Peter, Saffrich Rainer, Gröne Hermann-Josef, Debus Jürgen, Lipson Kenneth E, Abdollahi Amir
Department of Radiation Oncology, German Cancer Research Center, University of Heidelberg Medical School, Heidelberg Germany.
Cancer Res. 2005 May 1;65(9):3643-55. doi: 10.1158/0008-5472.CAN-04-1668.
It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.
有人提出，在双重抗癌策略组合中，化疗和放疗可以与抗血管生成疗法进行有利的联合。在此，我们研究了同时施用所有三种治疗方法的三联疗法的效果。我们发现，在体外和体内，由SU11657（一种多靶点小分子血管内皮生长因子和血小板衍生生长因子受体酪氨酸激酶抑制剂）、培美曲塞（一种多靶点叶酸抗代谢物）和电离辐射组成的三联疗法组合的抗内皮细胞和抗肿瘤效果优于所有单药和双药组合。在人脐静脉内皮细胞和肿瘤细胞（A431）中，三联疗法在细胞增殖、迁移、管腔形成、克隆形成存活和凋亡检测（亚G1期和半胱天冬酶-3评估）中的优势明显。在探索对细胞存活信号通路的潜在影响时，我们发现辐射和化疗可诱导内皮细胞Akt磷酸化，但SU11657在体外和体内可减弱在BALB/c裸鼠皮下生长的A431人肿瘤异种移植瘤中的这一过程。三联疗法进一步降低了肿瘤细胞增殖（Ki-67指数）和血管计数（CD31染色），与所有其他治疗方案相比，诱导了更大的肿瘤生长延迟，且未增加明显毒性。在测试A431肿瘤的不同治疗方案时，我们发现，在开始SU11657治疗后给予放疗（单次剂量7.5 Gy）的方案比在SU11657治疗前给予放疗更有效。因此，我们发现SU11657在1天后可将瘤内间质液压力从8.8±2.6显著降低至4.2±1.5 mmHg。同样，定量T2加权磁共振成像测量显示，接受SU11657治疗的小鼠瘤内水肿减轻。我们的数据表明，用SU11657进行抗血管生成治疗抑制Akt信号通路可能导致：（a）肿瘤血管正常化，这为后续放疗/化疗创造了必要的生理条件，以及（b）使内皮细胞对放疗/化疗直接重新敏感。我们得出结论，联合抗血管生成、化疗和放疗的三联癌症疗法具有有益的分子和生理效应，有望成为一种临床相关的抗肿瘤策略。
