Devy Laetitia, de Groot Franciscus M H, Blacher Silvia, Hajitou Amin, Beusker Patrick H, Scheeren Hans W, Foidart Jean-Michel, Noël Agnès
Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège, Belgium.
FASEB J. 2004 Mar;18(3):565-7. doi: 10.1096/fj.03-0462fje. Epub 2004 Jan 20.
To generate doxorubicin (Dox) specifically at the tumor site, the chemotherapeutic agent was incorporated into a prodrug by linkage to a peptide specifically recognized by plasmin, which is overproduced in many cancers. ST-9905, which contains an elongated self-elimination spacer, is activated more rapidly in vitro by plasmin than is ST-9802. Prodrug activation in vitro depended on the level of urokinase produced by tumor cells and was inhibited by aprotinin, a plasmin inhibitor. Comparison of equimolar concentrations of ST-9905, ST-9802, and Dox in EF43.fgf-4 and MCF7 models revealed that both prodrugs, in sharp contrast to Dox, displayed antiproliferative and antiangiogenic activities without discernible toxicity. Although MCF7 cells are poor urokinase producers in vitro, prodrug efficacy in this model may be explained by production of plasmin by tumor-infiltrating host cells. Mice treated with equitoxic concentrations (maximum tolerated doses) of prodrugs showed 100% survival and negligible body weight loss, in contrast to results after Dox treatment. ST-9905 was substantially more effective than ST-9802 and induced similar tumor growth inhibition as Dox but without apparent toxicity. This finding may be explained by the elongated spacer, which facilitates enzymatic prodrug activation. These data validate both the use of elongated spacers in vivo and the concept of targeting anticancer prodrugs to tumor-associated plasmin.
为了在肿瘤部位特异性地生成阿霉素（Dox），将这种化疗药物与一种可被纤溶酶特异性识别的肽连接，从而制成前药，纤溶酶在许多癌症中都会过量产生。ST - 9905含有一个延长的自消除间隔区，在体外被纤溶酶激活的速度比ST - 9802更快。前药在体外的激活取决于肿瘤细胞产生的尿激酶水平，并受到纤溶酶抑制剂抑肽酶的抑制。在EF43.fgf - 4和MCF7模型中对等摩尔浓度的ST - 9905、ST - 9802和Dox进行比较，结果显示，与Dox形成鲜明对比的是，这两种前药均表现出抗增殖和抗血管生成活性，且无明显毒性。尽管MCF7细胞在体外产生尿激酶的能力较弱，但该模型中前药的疗效可能是由肿瘤浸润的宿主细胞产生纤溶酶来解释的。与Dox治疗后的结果相比，用等毒性浓度（最大耐受剂量）的前药治疗的小鼠存活率为100%，体重减轻可忽略不计。ST - 9905比ST - 9802有效得多，诱导的肿瘤生长抑制与Dox相似，但无明显毒性。这一发现可能是由于延长的间隔区促进了前药的酶促激活。这些数据证实了延长间隔区在体内的应用以及将抗癌前药靶向肿瘤相关纤溶酶这一概念的有效性。
