Department of Tumor Biology and Angiogenesis, Genentech Inc., South San Francisco, CA 94080, USA.
Clin Cancer Res. 2010 Aug 1;16(15):3887-900. doi: 10.1158/1078-0432.CCR-09-3100. Epub 2010 Jun 16.
Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth.
We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density.
Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates.
In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped.
血管内皮生长因子（VEGF）轴的抑制是所有已批准的抗血管生成治疗的基础。在临床前模型中，抗 VEGF 阻断抗体表现出广泛的疗效，这取决于肿瘤的背景和治疗持续时间。我们旨在描述这种活性，并评估治疗中断对肿瘤再生长动力学的影响。
我们评估了抗 VEGF 治疗对 30 个异种移植模型和癌症的遗传小鼠模型中肿瘤生长和存活的影响。组织学分析用于评估治疗对肿瘤血管的影响。我们使用了各种治疗方案，以分析治疗持续时间和停药对生长速度、存活和血管密度的影响。
临床前肿瘤模型的特点是对 VEGF 的不同依赖性，从而确定了测试可能补充或增强抗 VEGF 治疗的其他药物的模型。我们还发现，更长时间的抗 VEGF 单克隆抗体暴露可延迟细胞移植和遗传肿瘤模型中已建立肿瘤的生长，并防止细胞消融治疗后一部分残留肿瘤的再生长。在已建立的肿瘤中停止抗 VEGF 治疗会导致肿瘤以比对照治疗动物更慢的速度生长，没有加速肿瘤生长或反弹的证据。然而，在停止某些化疗后，会观察到更快的再生长。同时给予抗 VEGF 似乎使这些加速的生长速率正常化。
在不同的临床前模型中，作为单一药物、与化疗联合使用或在化疗停止后作为维持治疗，持续的 VEGF 抑制提供了最大的益处。
