PURPOSE: Anthrax Lethal Toxin (LeTx), composed of protective antigen and lethal factor, catalytically cleaves mitogen-activated protein kinase (MAPK) kinases and inhibits the MAPK signaling pathways. The majority of metastatic melanomas possess the V599E BRAF mutation, which constitutively activates MAPK1/2 signaling. LeTx is cytotoxic to BRAF mutant melanoma cell lines in vitro, whereas most normal cells are resistant to this toxin. In this study, we determine the in vivo potency and safety of systemically administered LeTx. EXPERIMENTAL DESIGN: A s.c. xenograft melanoma model in athymic nude mice was treated with different i.p. doses of LeTx. RESULTS: In this study, we show that in vivo systemic LeTx treatment of s.c. xenograft melanoma tumors in athymic nude mice yields partial and complete tumor regressions with minor toxicity to mice. When animal toxicity was observed, we did not find any histologic evidence of tissue damage. CONCLUSIONS: LeTx is one of the rare targeted agents to produce complete remissions of human melanomas in an animal model and thus warrants further preclinical development.
PURPOSE:Anthrax Lethal Toxin (LeTx), composed of protective antigen and lethal factor, catalytically cleaves mitogen-activated protein kinase (MAPK) kinases and inhibits the MAPK signaling pathways. The majority of metastatic melanomas possess the V599EBRAF mutation, which constitutively activates MAPK1/2 signaling. LeTx is cytotoxic to BRAF mutant melanoma cell lines in vitro, whereas most normal cells are resistant to this toxin. In this study, we determine the in vivo potency and safety of systemically administered LeTx. EXPERIMENTAL DESIGN: A s.c. xenograft melanoma model in athymic nude mice was treated with different i.p. doses of LeTx. RESULTS: In this study, we show that in vivo systemic LeTx treatment of s.c. xenograft melanoma tumors in athymic nude mice yields partial and complete tumor regressions with minor toxicity to mice. When animal toxicity was observed, we did not find any histologic evidence of tissue damage. CONCLUSIONS: LeTx is one of the rare targeted agents to produce complete remissions of humanmelanomas in an animal model and thus warrants further preclinical development.
Authors: Mi Young Yang; Amit Chaudhary; Steven Seaman; Jill Dunty; Janine Stevens; Mohammed K Elzarrad; Arthur E Frankel; Brad St Croix Journal: Biochim Biophys Acta Date: 2010-12-01
Authors: Elias Kassab; Manal Darwish; Zahra Timsah; Shihui Liu; Stephen H Leppla; Arthur E Frankel; Ralph J Abi-Habib Journal: Transl Oncol Date: 2013-02-01 Impact factor: 4.243
Authors: Randall W Alfano; Stephen H Leppla; Shihui Liu; Thomas H Bugge; Janelle M Ortiz; Terry C Lairmore; Nicholas S Duesbery; Ian C Mitchell; Fiemu Nwariaku; Arthur E Frankel Journal: Mol Cancer Ther Date: 2010-01-06 Impact factor: 6.261
Authors: Mike Cullen; Steven Seaman; Amit Chaudhary; Mi Young Yang; Mary Beth Hilton; Daniel Logsdon; Diana C Haines; Lino Tessarollo; Brad St Croix Journal: Cancer Res Date: 2009-07-21 Impact factor: 12.701
Authors: Shihui Liu; Hailun Wang; Brooke M Currie; Alfredo Molinolo; Howard J Leung; Mahtab Moayeri; John R Basile; Randall W Alfano; J Silvio Gutkind; Arthur E Frankel; Thomas H Bugge; Stephen H Leppla Journal: J Biol Chem Date: 2007-11-01 Impact factor: 5.157
Authors: Diane E Peters; Benjamin Hoover; Loretta Grey Cloud; Shihui Liu; Alfredo A Molinolo; Stephen H Leppla; Thomas H Bugge Journal: Toxicol Appl Pharmacol Date: 2014-06-24 Impact factor: 4.219