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Anthrax prodrug: this uPA-activatable pro-drug has an effect on primary tumour growth in syngenic transplanted tumours in mice

A potent prodrug PrAg-U2 consists of modified anthrax toxins that are activated on the cell surface by receptor-bound uPA leading to the sequential events of internalization of the added recombinant cytotoxin, FP59, leading to cell death.

We have now investigated the systemic antitumour efficacy of PrAg-U2 + FP59. C57Bl/6J mice bearing syngenic tumours derived from B16 melanoma, T241 fibrosarcoma, or Lewis lung carcinoma cells were treated with different mass ratios and doses of PrAg-U2 + FP59.

There was a significant antitumour effect of systemic administration of PrAg-U2 + FP59 in the three syngenic tumour models. Optimal antitumour effect and low toxicity was obtained with a 25:1 mass ratio between the two components (PrAg-U2 and FP59). PrAg-U2 + FP59 displays a clear dose-response relationship with regard to both antitumour efficacy and systemic toxicity (1).

The systemic toxicity of the prodrug can be a problem. However, administration of murine monoclonal antibodies against murine uPAR could attenuate the lethality induced by systemic administration of too high doses of PrAg-U2 + FP59 in mice (2).

1. Rono B, Romer J, Liu S, Bugge TH, Leppla SH, Kristjansen PE. Antitumor efficacy of a urokinase activation-dependent anthrax toxin. Mol Cancer Ther 2006;5:89-96.

2. Pass J, Jögi A, Lund IK, Rønø B, Rasch MG, Gårdsvoll H, Lund LR, Ploug M, Rømer J, Danø K and Høyer-Hansen G - Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: Inhibitory effects on receptor- mediated uPA activity in vitro and in vivo. Thromb Haem, 97(5): in press, 2007

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Finsen Laboratory, RIGSHOSPITALET
Ole Maaløes Vej 5, Building 3, 3, Copenhagen Biocente
2200 Copenhagen
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