Systemic anthrax lethal toxin therapy produces regressions of subcutaneous human melanoma tumors in athymic nude mice

Ralph J. Abi-Habib, Ravibhushan Singh, Stephen H. Leppla, John J. Greene, Yan Ding, Bree Berghuis, Nicholas S. Duesbery, Arthur E. Frankel

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7437-7443
Number of pages7
JournalClinical Cancer Research
Volume12
Issue number24
DOIs
Publication statusPublished - Dec 15 2006

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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