Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model
Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model
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DOI：
10.1158/1535-7163.mct-07-2122
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发表时间：
2008-03-01
影响因子：
5.7
通讯作者：
Vinals, Francesc
中科院分区：
文献类型：
--
作者：
Laquente, Berta;Lacasa, Cristina;Vinals, Francesc
吉西他滨由于其对增殖细胞的细胞毒性作用而显示出显著的抗肿瘤作用。在这篇文章中，我们的目的是调查潜在的抗肿瘤和抗血管生成作用的吉西他滨的节拍时间表，涉及定期管理的剂量低于标准治疗的细胞毒性药物。体外实验结果显示，人内皮细胞对吉西他滨的敏感性（IC 50 3 nmol/L）高于胰腺癌细胞（IC 50 20 nmol/L）。在体内研究中，我们使用了人胰腺癌裸鼠原位移植模型。吉西他滨按照低剂量方案（1 mg/kg/d，持续1个月）进行i. p.给药，并与常规方案（100 mg/kg，植入后第0、3、6和9天）进行比较。对已建立肿瘤的节拍治疗效果与标准给药相当。CD 31内皮标记面积的测量使我们能够显示该药物的体内抗血管生成作用，该作用通过使用节拍给药进一步增强。这种效应与血小板反应蛋白-1（一种天然的血管生成抑制剂）的诱导相关。我们的研究结果使我们能够假设，除了直接的抗增殖或细胞毒性抗内皮细胞作用外，涉及血小板反应蛋白-1诱导的次要作用可能为节拍吉西他滨治疗的特异性作用提供解释。
Gemcitabine shows a marked antitumor effect as a result of its cytotoxic action toward proliferative cells. In this article, we aim to investigate the potential antitumor and antiangiogenic effect of gemcitabine following a metronomic schedule that involves the regular administration of cytotoxic drugs at doses lower than standard treatment. In vitro results showed that human endothelial cells are more sensitive to gemcitabine (IC50 3 nmol/L) than pancreatic tumor cells (IC50 20 nmol/L). For in vivo studies, we used an orthotopic implantation model of human pancreatic carcinoma in nude mice. Gemcitabine was administered i.p. following a low-dose schedule (1 mg/kg/d for a month) and compared with the conventional schedule (100 mg/kg days 0, 3, 6, and 9 postimplantation). Metronomic treatment effect on established tumor was equivalent to standard administration. The measure of CD31 endothelial marked area allowed us to show an in vivo antiangiogenic effect of this drug that was further enhanced by using metronomic administration. This effect correlated with an induction of thrombospondin-1, a natural inhibitor of angiogenesis. Our results allow us to hypothesize that, in addition to a direct anti proliferative or cytotoxic antiendothelial cell effect, a secondary effect involving thrombospondin-1 induction might provide an explanation for the specificity of the effects of metronomic gemcitabine treatment.