Monotherapy with a tumor-targeting mutant of S. typhimurium inhibits liver metastasis in a mouse model of pancreatic cancer.
Cancer of the exocrine pancreas is the fourth leading cause of cancer deaths in the United States. Currently, surgical resection is the only hope for cure. The majority of patients present with locally-advanced or metastatic disease. The most common site for distant metastasis is the liver. We report here a modified auxotrophic strain of S. typhimurium that can target and inhibit the growth of liver metastasis in a mouse model of pancreatic cancer. This strain of S. typhimurium is auxotrophic (leucine-arginine dependent) but apparently receives sufficient nutritional support from tumor tissue. To increase tumor targeting ability and tumor killing efficacy, this strain was further modified by re-isolation from a tumor growing in a nude mouse and termed A1-R. In the present study, we demonstrate the efficacy of locally- as well as systemically-administered A1-R on liver metastasis of pancreatic cancer. Mice treated with A1-R given locally via intrasplenic injection or systemically via tail vein injection had a much lower hepatic and splenic tumor burden compared with control mice. Systemic treatment with intravenous A1-R also increased survival time. All results were statistically significant. This study suggests the clinical potential of bacterial treatment of a critical metastatic target of pancreatic cancer.
Yam
Clinton
C
AntiCancer, Inc., San Diego, California, USA.
Zhao
Ming
M
Hayashi
Katsuhiro
K
Ma
Huaiyu
H
Kishimoto
Hiroyuki
H
McElroy
Michele
M
Bouvet
Michael
M
Hoffman
Robert M
RM
D000818:Animals; D004195:Disease Models, Animal; D014644:Genetic Variation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009604:Nitrosoguanidines / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000382:microbiology / Q000601:surgery* / Q000628:therapy; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D014162:Transfection / Q000379:methods
D009604:Nitrosoguanidines