title: Perfusion Pressure Is a Critical Determinant of the Intratumoral Extravasation of Oncolytic Viruses.
abstract: Antitumor efficacy of oncolytic virotherapy is determined by the density and distribution of infectious centers within the tumor, which may be heavily influenced by the permeability and blood flow in tumor microvessels. Here, we investigated whether systemic perfusion pressure, a key driver of tumor blood flow, could influence the intratumoral extravasation of systemically administered oncolytic vesicular stomatitis virus (VSV) in myeloma tumor-bearing mice. Exercise was used to increase mean arterial pressure, and general anesthesia to decrease it. A recombinant VSV expressing the sodium iodide symporter (NIS), which concentrates radiotracers at sites of infection, was administered intravenously to exercising or anesthetized mice, and nuclear NIS reporter gene imaging was used to noninvasively track the density and spatial distribution of intratumoral infectious centers. Anesthesia resulted in decreased intratumoral infection density, while exercise increased the density and uniformity of infectious centers. Perfusion state also had a significant impact on the antitumor efficacy of the VSV therapy. In conclusion, quantitative dynamic radiohistologic imaging was used to noninvasively interrogate delivery of oncolytic virotherapy, highlighting the critical importance of perfusion pressure as a driver of intratumoral delivery and efficacy of oncolytic viruses.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Mayo Graduate School, Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nace
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Ayala-Breton C
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Steele
authors.affiliation: Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Bailey
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kah Whye
authors.initials: KW
authors.lastname: Peng
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: sjr@mayo.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D062186:Arterial Pressure; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D051379:Mice; D009101:Multiple Myeloma / Q000503:physiopathology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D010477:Perfusion; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014709:Vero Cells; D018116:Vesiculovirus / Q000502:physiology*; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters