Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

For the purpose of using LF as a targeted toxic polypeptide with superior specificity, a modified LeTx (PA-L1/LF) composed of LF and MMP activated PA protein was tested in mice xenograft models of human tumors. As expected, the PA-L1/LF showed lower toxicity to mice than wild-type toxin and has a potent anti-tumor activity. Surprisingly, anti-tumor activity was observed not only against human melanomas with B-Raf V600E mutation (due to direct toxicity against these cells), but also against other human tumor types including colon and lung carcinomas, and mouse tumors, regardless of their B-Raf status. Tumor histology and in vivo angiogenesis assays suggested that these effects can be attributed to indirect targeting of tumor vasculature and angiogenic processes (expression of MMPs has been shown to be upregulated in angiogenic lesions [486] [487] [488] [489] ), in which mitogen-activated protein kinase (MAPK) signaling pathways play a central role [422, 490] . Later in vitro studies on endothelial proliferation, invasion, and tube formation showed that activated LeTx acts by impairing microvascular endothelial cell invasion and migration in the absence of endothelial cell death [423] . Another intriguing observation was that the PA-L1/LF administration showed higher anti-tumor efficacy than does the wild-type toxin, probably because of greater bioavailability and longer half-life of PA-L1(relative to PA) in circulation [422] .