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


METHODS
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.
Abi-Habib
Ralph J
RJ
Cancer Research Institute, Scott & White Memorial Hospital, Temple, Texas 76502, USA.
Singh
Ravibhushan
R
Leppla
Stephen H
SH
Greene
John J
JJ
Ding
Yan
Y
Berghuis
Bree
B
Duesbery
Nicholas S
NS
Frankel
Arthur E
AE
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin