Ma Jie, Waxman David J
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA.
Mol Cancer Ther. 2008 Dec;7(12):3670-84. doi: 10.1158/1535-7163.MCT-08-0715.
Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. However, the survival benefits of antiangiogenic drugs have thus far been rather modest, stimulating interest in developing more effective ways to combine antiangiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between antiangiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Antiangiogenic drugs such as the anti-vascular endothelial growth factor antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of coadministered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of coadministered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where antiangiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase antitumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of antiangiogenic therapies and to identify responsive patients. New targets for antiangiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs.
血管生成是肿瘤发展和转移的一个标志，目前已成为癌症治疗的一个有效靶点。然而，迄今为止抗血管生成药物的生存获益相当有限，这激发了人们对开发更有效方法将抗血管生成药物与既定化疗方案联合使用的兴趣。本综述讨论了该领域的最新进展和新出现的挑战；研究了抗血管生成药物与传统化疗药物之间的相互作用，并探讨了优化联合治疗的策略。抗血管生成药物，如抗血管内皮生长因子抗体贝伐单抗，可诱导肿瘤血管系统的功能正常化，这种正常化是短暂的，并且可增强同时给予的放化疗的活性。然而，长期抑制血管生成通常会降低同时给予的化疗药物在肿瘤中的摄取，这表明需要探索新的方法，包括间歇性治疗方案和促血管生成策略，以增加化疗药物的暴露。在抗血管生成诱导的肿瘤细胞饥饿增强传统化疗药物的内在细胞毒性作用的情况下，联合治疗可能会增加抗肿瘤活性，尽管细胞毒性药物的暴露有所减少。随着新的血管生成抑制剂进入临床，需要可靠的替代标志物来监测抗血管生成治疗的进展并识别有反应的患者。抗血管生成的新靶点不断被发现，这增加了阻断肿瘤血管生成和规避长期使用这些药物可能出现的耐药机制的机会。
