Antitumor efficacy of a urokinase activation-dependent anthrax toxin.
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.
Rønø
Birgitte
B
Institute of Molecular Pathology, University of Copenhagen, Denmark.
Rømer
John
J
Liu
Shihui
S
Bugge
Thomas H
TH
Leppla
Stephen H
SH
Kristjansen
Paul E G
PE
D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000633:toxicity; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism*
D000942:Antigens, Bacterial; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin; D003907:Dexamethasone; D014568:Urokinase-Type Plasminogen Activator