Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel.

Abstract

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib.

• Authors: Alexander N Wein, Shihui Liu, Yi Zhang, Andrew T McKenzie, Stephen H Leppla
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 1 Pg. 206-12 (Feb 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 22843210 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antigens, Bacterial
• Antineoplastic Agents, Phytogenic
• Bacterial Toxins
• anthrax toxin
• Urokinase-Type Plasminogen Activator
• Paclitaxel

Topics

• Animals
• Antigens, Bacterial (administration & dosage)
• Antineoplastic Agents, Phytogenic (administration & dosage)
• Bacterial Toxins (administration & dosage)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Paclitaxel
• Skin Neoplasms (drug therapy, pathology)
• Tumor Burden (drug effects)
• Urokinase-Type Plasminogen Activator (administration & dosage)