Rønø Birgitte, Rømer John, Liu Shihui, Bugge Thomas H, Leppla Stephen H, Kristjansen Paul E G
Institute of Molecular Pathology, University of Copenhagen, Denmark.
Mol Cancer Ther. 2006 Jan;5(1):89-96. doi: 10.1158/1535-7163.MCT-05-0163.
Previously, we have generated a potent prodrug consisting of modified anthrax toxins that is activated by urokinase plasminogen activator (uPA). The cytotoxicity of the drug, PrAg-U2 + FP59, is dependent on the presence of receptor-associated uPA activity. Local intradermal administration of PrAg-U2 + FP59 adjacent to the tumor nodules in mice with transplanted solid tumors had a potent antitumor effect. In succession of these experiments, we have now investigated the systemic antitumor efficacy of PrAg-U2 + FP59. C57Bl/6J mice bearing syngenic tumors derived from B16 melanoma, T241 fibrosarcoma, or Lewis lung carcinoma cells were treated with different mass ratios and doses of PrAg-U2 + FP59. Tumor volumes were recorded daily by caliper measurements. In some experiments, dexamethasone was coadministered. Our data show a significant antitumor effect of systemic administration of PrAg-U2 + FP59 in three syngenic tumor models. Optimal antitumor effect and low toxicity was obtained with a 25:1 mass ratio between the two components (PrAg-U2 and FP59). The experiments show that PrAg-U2 + FP59 displays a clear dose-response relationship with regard to both antitumor efficacy and systemic toxicity. Dose-limiting toxicity seemed to be due to activation of the prodrug by uPA and its receptor in the intestinal mucosa. Concurrent treatment with dexamethasone was found to prevent dose-limiting toxicity. Taken together, these data indicate that uPA-activated toxins may be promising candidates for targeted therapy of human cancers that overexpress uPA and its receptor.
此前，我们制备了一种由修饰的炭疽毒素组成的强效前药，其可被尿激酶型纤溶酶原激活剂（uPA）激活。该药物PrAg-U2 + FP59的细胞毒性取决于受体相关uPA活性的存在。在移植了实体瘤的小鼠中，将PrAg-U2 + FP59局部皮内注射到肿瘤结节附近具有强效抗肿瘤作用。在这些实验的后续研究中，我们现在研究了PrAg-U2 + FP59的全身抗肿瘤疗效。用不同质量比和剂量的PrAg-U2 + FP59处理携带源自B16黑色素瘤、T241纤维肉瘤或Lewis肺癌细胞的同基因肿瘤的C57Bl/6J小鼠。每天用卡尺测量记录肿瘤体积。在一些实验中，同时给予地塞米松。我们的数据显示，在三种同基因肿瘤模型中，PrAg-U2 + FP59全身给药具有显著的抗肿瘤作用。两种成分（PrAg-U2和FP59）的质量比为25:1时，可获得最佳抗肿瘤效果且毒性较低。实验表明，PrAg-U2 + FP59在抗肿瘤疗效和全身毒性方面均呈现明显的剂量反应关系。剂量限制性毒性似乎是由于前药在肠黏膜中被uPA及其受体激活所致。发现同时用地塞米松治疗可预防剂量限制性毒性。综上所述，这些数据表明，uPA激活的毒素可能是过表达uPA及其受体的人类癌症靶向治疗的有前景的候选药物。
