Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, S-217 Research Building, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Nat Rev Clin Oncol. 2011 Mar 1;8(4):210-21. doi: 10.1038/nrclinonc.2011.21.
Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development.
针对血管内皮生长因子（VEGF）通路的抗血管生成药物已使部分患者的转移性疾病进展速度减缓，与对照组相比，这些药物具有无进展生存期（PFS）和总生存期获益。然而，这些结果比大多数临床前测试预测的要温和，PFS 获益通常并不伴有总生存期的改善。人们对耐药性的基础和预测性临床前模型的局限性提出了质疑，也对血管生成抑制治疗后疾病进展的性质是否与经典细胞毒性治疗不同提出了质疑——特别是治疗是否可能导致更具侵袭性或转移性的行为。此外，由于抗血管生成治疗在早期疾病患者中的临床试验失败，以及目前有数百项针对围手术期新辅助和辅助治疗的临床试验正在进行，人们现在更加意识到在这些研究之前缺乏适当的临床前测试。提高对转移性疾病所有阶段的临床前评估应该是未来抗血管生成药物发现和开发的优先事项。
