title: Bacterial delivery of Staphylococcus aureus α-hemolysin causes regression and necrosis in murine tumors.
abstract: Bacterial therapies, designed to manufacture therapeutic proteins directly within tumors, could eliminate cancers that are resistant to other therapies. To be effective, a payload protein must be secreted, diffuse through tissue, and efficiently kill cancer cells. To date, these properties have not been shown for a single protein. The gene for Staphylococcus aureus α-hemolysin (SAH), a pore-forming protein, was cloned into Escherichia coli. These bacteria were injected into tumor-bearing mice and volume was measured over time. The location of SAH relative to necrosis and bacterial colonies was determined by immunohistochemistry. In culture, SAH was released and killed 93% of cancer cells in 24 hours. Injection of SAH-producing bacteria reduced viable tissue to 9% of the original tumor volume. By inducing cell death, SAH moved the boundary of necrosis toward the tumor edge. SAH diffused 6.8 ± 0.3 µm into tissue, which increased the volume of affected tissue from 48.6 to 3,120 µm(3). A mathematical model of molecular transport predicted that SAH efficacy is primarily dependent on colony size and the rate of protein production. As a payload protein, SAH will enable effective bacterial therapy because of its ability to diffuse in tissue, kill cells, and expand tumor necrosis.
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA; Current Address: Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: St Jean
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Swofford
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Jan T
authors.initials: JT
authors.lastname: Panteli
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Brentzel
authors.affiliation: Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA. Electronic address: forbes@ecs.umass.edu.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Forbes
mesh_terms: D000818:Animals; D005260:Female; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice; D009336:Necrosis / Q000209:etiology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism*
chemical_list: D006460:Hemolysin Proteins