title: Salmonella-based tumor-targeted cancer therapy: tumor amplified protein expression therapy (TAPET) for diagnostic imaging.
abstract: In preclinical studies, genetically engineered Salmonella have the ability to localize, selectively accumulate, and persist within transplantable murine tumors, spontaneous murine tumors and human tumor xenographs, and can express therapeutic proteins at high levels. These strains of engineered non-virulent Salmonella typhimurium display the capacity to accumulate and grow selectively in a variety of tumor types and to inhibit the growth of primary and metastatic tumors following intravenous injection into tumor-bearing mice. One strain of the bacteria (VNP20009) which has endogenous antitumor activity is currently in Phase I clinical trials. The bacteria are highly attenuated and genetically stable. The combination of the lipid mutation and the purine auxotrophy attenuate the virulence of the bacteria by greater than 10000-fold and enhance the specificity of the bacteria for tumor tissue. These bacteria have been found to be safe in mice, pigs and monkeys when administered intravenously. Second-generation Salmonella vectors will be developed to include transgenes that will express therapeutic agents and reporter transgenes for non-invasive imaging. We have performed a preliminary study to demonstrate localization of [(14)C]FIAU in tumored mice pretreated with Salmonella expressing HSV1-TK. The [(14)C]FIAU radioactivity and bacterial count data strongly support a Salmonella(TK)-dependent [(14)C]FIAU accumulation of at least 30-fold higher in tumor tissue compared to muscle tissue. These data warrant further investigation on the use of genetically engineered Salmonella as a systemically administered tumor-specific agents for tumor therapy and delivery of diagnostic imaging markers.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tjuvajev
authors.forename: R
authors.initials: R
authors.lastname: Blasberg
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: L M
authors.initials: LM
authors.lastname: Zheng
authors.forename: I
authors.initials: I
authors.lastname: King
authors.forename: D
authors.initials: D
authors.lastname: Bermudes
mesh_terms: D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005819:Genetic Markers; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012475:Salmonella / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D005819:Genetic Markers; D001086:Arabinofuranosyluracil; C043457:fialuridine; D011505:Protein-Tyrosine Kinases