Efficacy of Salmonella typhimurium A1-R versus chemotherapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX)

J Cell Biochem. 2014 Jul;115(7):1254-61. doi: 10.1002/jcb.24769.

Abstract

The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on pancreatic cancer patient-derived orthotopic xenografts (PDOX). The PDOX model was originally established from a pancreatic cancer patient in SCID-NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)-expressing stroma for the purpose of imaging the tumor after passage to non-transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1-R or standard chemotherapy, including gemcitabine (GEM), which is first-line therapy for pancreatic cancer, for comparison of efficacy. A1-R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (P = 0.011), with comparable efficacy of GEM, CDDP, and 5-FU. Histopathological response to treatment was defined according to Evans's criteria and A1-R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1-R is effective against a very low-passage patient tumor, in this case, pancreatic cancer. The data of the present report suggest A1-1 will have clinical activity in pancreatic cancer, a highly lethal and treatment-resistant disease and may be most effectively used in combination with other agents.

Keywords: FLUORESCENT PROTEINS; IMAGING; NUDE MICE; ORTHOTOPIC; PANCREATIC CANCER; PDOX; RFP; Salmonella typhimurium.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Cisplatin / therapeutic use
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Disease Models, Animal
  • Fluorouracil / therapeutic use
  • Humans
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / therapy*
  • Salmonella Infections / pathology*
  • Salmonella typhimurium / pathogenicity*
  • Transplantation, Heterologous
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Luminescent Proteins
  • red fluorescent protein
  • Deoxycytidine
  • gemcitabine
  • Cisplatin
  • Fluorouracil