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¹ Institute of Molecular Pathology, University of Copenhagen; ² Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark; ³ Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases; and ⁴ Proteases and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland

Requests for reprints: John Rømer, Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Phone: 45-3545-5875; Fax: 45-3538-5450. E-mail: jromer{at}finsenlab.dk

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]

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Received 5/18/05; revised 10/19/05; accepted 11/ 4/05.

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