Wang Yan, Xu Jian-ming, Xu Qin-zhi, Zhou Ping-kun, Song San-tai
GI Cancer Department, Cancer Center of 307 Hospital of PLA, Beijing 100071, China.
Zhonghua Zhong Liu Za Zhi. 2009 Oct;31(10):746-851.
To observe the anti-proliferation effect of bevacizumab and SN-38 (active metabolite of irinotecan), and investigate the possible mechanisms of these two agents.
Human colon cancer LoVo cells were cultured under hypoxic conditions. Inhibition of cell proliferation was evaluated by MTT assay. The drug modulation on HIF-1alpha, VEGF, ERK and AKT were assessed by the following assays. The mRNA expression of HIF-1alpha and VEGF were measured by RT-PCR. The protein expression of HIF-1alpha, ERK and AKT were evaluated by Western blot analysis, and VEGF by ELISA assay.
Among different combination schedules, Bevacizumab given after SN-38 show most synergistic anti-proliferation effect. Under hypoxic conditions, the expression of HIF-1alpha and VEGF increased as time accumulated, Bevacizumab combined with SN-38 almost completely inhibited the expression of HIF-1alpha and VEGF. Moreover, the MAP kinase pathway was involved in the drug modulation of HIF-1alpha and VEGF.
These findings suggest the anti-proliferation effect of bevacizumab and SN-38 was schedule-dependent, and the synergistic effect of Bevacizumab and SN-38 was related to drug modulation of the HIF-1alpha and MAP kinase pathway.
观察贝伐单抗和伊立替康的活性代谢产物SN - 38的抗增殖作用，并探讨这两种药物的可能作用机制。
将人结肠癌LoVo细胞在缺氧条件下培养。采用MTT法评估细胞增殖抑制情况。通过以下实验评估药物对HIF - 1α、VEGF、ERK和AKT的调节作用。采用RT - PCR法检测HIF - 1α和VEGF的mRNA表达。采用蛋白质印迹分析评估HIF - 1α、ERK和AKT的蛋白质表达，采用ELISA法评估VEGF。
在不同的联合给药方案中，SN - 38后给予贝伐单抗显示出最显著的协同抗增殖作用。在缺氧条件下，HIF - 1α和VEGF的表达随时间积累而增加，贝伐单抗联合SN - 38几乎完全抑制了HIF - 1α和VEGF的表达。此外，MAP激酶途径参与了药物对HIF - 1α和VEGF的调节。
这些发现表明贝伐单抗和SN - 38的抗增殖作用具有给药方案依赖性，且贝伐单抗和SN - 38的协同作用与药物对HIF - 1α和MAP激酶途径的调节有关。
