Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: implications for broad anti-tumor efficacy.
Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase (MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin (LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.
Alfano
Randall W
RW
Cancer Research Institute of Scott & White Memorial Hospital, Temple, Texas 76502, USA.
Leppla
Stephen H
SH
Liu
Shihui
S
Bugge
Thomas H
TH
Duesbery
Nicholas S
NS
Frankel
Arthur E
AE
D000942:Antigens, Bacterial / Q000378:metabolism / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases