Ropert Stanislas, Mir Olivier, Armand Jean-Pierre
Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris.
Bull Cancer. 2007 Jul;94 Spec No:S180-90.
Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis. Inhibiting angiogenesis is now a validated strategy for treatment of cancer. In order to do it, different ways are under investigation from cellular therapy to oral agents. Nowadays targeting angiogenesis with small molecules mainly concern inhibition of the VEGF receptors tyrosine kinase activity. Five molecules are currently in phase III trials and two of them (sunitinib and sorafenib) have been approved by the FDA for the treatment of advanced renal cancer. Despite those encouraging results, numerous points remain unclear. The toxicity profile seems to be favourable but long term effects could be problematic. Indeed, clinical trials have pointed out the role of VEGF pathway in the maintenance of numerous physiological functions. Moreover, none of the agents are specifically anti-angiogenic and the respective parts of the "off target" effects are difficult to evaluate. Simple and reliable surrogate markers of toxicity and efficacy are still lacking.
血管生成虽不会引发恶性肿瘤,但会促进肿瘤进展和转移。抑制血管生成现已成为一种经过验证的癌症治疗策略。为实现这一目标,从细胞疗法到口服药物,各种不同的方法都在研究之中。如今,利用小分子靶向血管生成主要涉及抑制血管内皮生长因子(VEGF)受体酪氨酸激酶活性。目前有五种分子正处于III期试验阶段,其中两种(舒尼替尼和索拉非尼)已获美国食品药品监督管理局(FDA)批准用于治疗晚期肾癌。尽管取得了这些令人鼓舞的结果,但仍有许多问题尚不清楚。毒性特征似乎较为良好,但长期影响可能存在问题。事实上,临床试验已指出VEGF通路在维持多种生理功能中的作用。此外,没有一种药物是特异性抗血管生成的,“脱靶”效应各自所占的比例难以评估。仍然缺乏简单可靠的毒性和疗效替代标志物。