Antitumor efficacy of a urokinase activation–dependent anthrax toxin

• Published in: Molecular cancer therapeutics 2006-01, Vol.5 (1), p.89-96
• Main Authors: Rønø, Birgitte, Rømer, John, Liu, Shihui, Bugge, Thomas H, Leppla, Stephen H, Kristjansen, Paul E G
• Format: Article
• Language: English
• Subjects: Animals; anthrax toxin; Antigens, Bacterial - pharmacology; Antigens, Bacterial - toxicity; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; antitumor; Bacterial Toxins - pharmacology; Bacterial Toxins - toxicity; Carcinoma, Lewis Lung - drug therapy; Dexamethasone - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Male; Mice; Mice, Inbred C57BL; Prodrugs - chemistry; Prodrugs - pharmacology; Recombinant Fusion Proteins - pharmacology; targeted therapy; uPA; uPAR; Urokinase-Type Plasminogen Activator - drug effects; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 1535-7163; 1538-8514
• 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. [Mol Cancer Ther 2006;5(1):89–96]