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Antitumor efficacy of a urokinase activation-dependent anthrax toxin.
Rønø, Birgitte; Rømer, John; Liu, Shihui; Bugge, Thomas H; Leppla, Stephen H; Kristjansen, Paul E G.
Afiliação
  • Rønø B; Institute of Molecular Pathology, University of Copenhagen, Denmark.
Mol Cancer Ther ; 5(1): 89-96, 2006 Jan.
Article em En | MEDLINE | ID: mdl-16432166
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.
Assuntos
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Base de dados: MEDLINE Assunto principal: Toxinas Bacterianas / Pró-Fármacos / Ativador de Plasminogênio Tipo Uroquinase / Antígenos de Bactérias / Antineoplásicos Limite: Animals Idioma: En Ano de publicação: 2006 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Toxinas Bacterianas / Pró-Fármacos / Ativador de Plasminogênio Tipo Uroquinase / Antígenos de Bactérias / Antineoplásicos Limite: Animals Idioma: En Ano de publicação: 2006 Tipo de documento: Article