Guo Yan tong, Ding Lei, Li Tian hong
Department of Surgery, Fourth Clinical Medical College of Peking University, Beijing, China.
Beijing Da Xue Xue Bao Yi Xue Ban. 2012 Oct 18;44(5):708-14.
Tumor angiogenesis defines tumor growth as it is dependent on generation of new blood vessels. Over forty years ago, Folkman hypothesized that inhibiting tumor angiogenesis could inhibit the growth of solid tumors and thus could be exploited as a therapeutic strategy. Among the numerous factors have been implicated in the angiogenesis activation process, vascular endothelial growth factor (VEGF) is the best studied angiogenesis target in cancer, using many different approaches in a wide variety of human cancers. Bevacizumab is the first anti-VEGF monoclonal antibody and proof-of-concept angiogenesis inhibitor that has been approved by the United States FDA for several tumor types. Drugs inhibiting VEGF work through several mechanisms, including inhibition of tumor blood vessel growth, vascular renormalization, potentiating of other antitumor agents, and inhibiting tumor metastasis. Unlike colorectal, kidney, lung, and brain tumors, the use of bevacizumab in breast cancer has been, as it were, on a rollercoaster in the United States, from accelerated approval for early drug access by patients in February 2008, to modest efficacy that fell short of high expectations, and increasing concern for serious toxicity in July 2010, and on to FDA revocation of accelerated approval for metastatic breast cancer patients in November 2011. Through a concise review of the FDA process, we have summarized its lessons, the challenges in developing new cancer drugs, and perspectives on further development of bevacizumab and other angiogenesis inhibitors in treatment of breast cancer. Despite all the challenges, antiangiogenesis remains a promising strategy to conquer breast cancer.
肿瘤血管生成决定肿瘤生长，因为它依赖于新血管的生成。四十多年前，福克曼提出假说，抑制肿瘤血管生成可以抑制实体瘤的生长，因此可作为一种治疗策略。在血管生成激活过程中涉及的众多因素中，血管内皮生长因子（VEGF）是癌症中研究得最透彻的血管生成靶点，在多种人类癌症中采用了许多不同方法进行研究。贝伐单抗是首个抗VEGF单克隆抗体和概念验证性血管生成抑制剂，已获美国食品药品监督管理局（FDA）批准用于多种肿瘤类型。抑制VEGF的药物通过多种机制发挥作用，包括抑制肿瘤血管生长、使血管正常化、增强其他抗肿瘤药物的作用以及抑制肿瘤转移。与结直肠癌、肾癌、肺癌和脑肿瘤不同，在美国，贝伐单抗在乳腺癌治疗中的应用可谓像坐过山车一样，从2008年2月加速批准患者早期用药，到疗效未达高期望的适度疗效，再到2010年7月对严重毒性的日益担忧，直至2011年11月FDA撤销对转移性乳腺癌患者的加速批准。通过对FDA审批过程的简要回顾，我们总结了其中的经验教训、开发新型抗癌药物面临的挑战，以及贝伐单抗和其他血管生成抑制剂在乳腺癌治疗中进一步发展的前景。尽管面临所有这些挑战，抗血管生成仍然是攻克乳腺癌的一种有前景的策略。
