O'Dwyer Peter J
Abramson Cancer Center, University of Pennsylvania, 51 N 39th Street, MAB-103, Philadelphia, Pennsylvania 19104, USA.
Oncologist. 2006 Oct;11(9):992-8. doi: 10.1634/theoncologist.11-9-992.
The level of angiogenic activity in colorectal tumors has been shown to be a determinant of survival. Recent trials established that, in both the first- and second-line treatment of metastatic colorectal cancer, the addition of the vascular endothelial growth factor (VEGF)-directed antibody bevacizumab to chemotherapy significantly prolongs survival compared to chemotherapy alone. Those trials provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Oral agents directed toward VEGF receptor signaling are in advanced development, but none to date has proven beneficial in phase III trials in advanced colorectal cancer. Additional trials are needed to determine if improved pharmacological characteristics of the small molecules can be modified to replicate the activity of the antibody or if mechanistic differences require a more specific approach. Since bevacizumab has minimal activity as a single agent, a key question for future therapeutic development relates to the interaction between antiangiogenic strategies and cytotoxic therapies. We hypothesize that bevacizumab may potentiate the efficacy of cytotoxics not solely by alterations of tumor interstitial pressure but also by promoting sensitivity to proapoptotic signals consequent upon nutrient and oxygen withdrawal.
结直肠癌中的血管生成活性水平已被证明是生存的一个决定因素。近期试验表明，在转移性结直肠癌的一线和二线治疗中，相比于单纯化疗，在化疗中添加血管内皮生长因子（VEGF）导向抗体贝伐单抗可显著延长生存期。这些试验提供了原理证明，即抑制血管生成有可能提高这种疾病的治疗效果。针对VEGF受体信号传导的口服药物正处于后期研发阶段，但迄今为止，在晚期结直肠癌的III期试验中尚无一种药物被证明有益。需要进行更多试验，以确定小分子药物改善后的药理学特性能否被调整以复制抗体的活性，或者机制差异是否需要更具针对性的方法。由于贝伐单抗作为单一药物活性极小，未来治疗发展的一个关键问题涉及抗血管生成策略与细胞毒性疗法之间的相互作用。我们假设，贝伐单抗可能不仅通过改变肿瘤间质压力，还通过促进对因营养和氧气供应中断而产生的促凋亡信号的敏感性来增强细胞毒性药物的疗效。
