title: RRx-001, an epigenetic-based radio- and chemosensitizer, has vascular normalizing effects on SCCVII and U87 tumors.
abstract: BACKGROUND
  The tumor-specific microregional effects of the anticancer agent RRx-001, a novel epigenetic-based radio/chemosensitizer with nitrogen oxide-donating properties in phase II clinical trials, were investigated with whole tissue section quantitative immunohistological staining in mouse SCCVII and human U87 tumors.
  
  
  RESULTS
  SCCVII tumors exhibited regions of intermittent perfusion exemplified by co-localization of vessels with the hypoxia marker pimonidazole commonly occurring throughout the tissue. A moderate increase in perfusion (21 to 28 %) was observed after a bolus dose of the perivascular stain DiOC7(3), however, with the absence of an increase in tissue oxygenation. U87 tumors showed an absence of blood flow over large areas of treated tumors after dosing with RRx-001. However, these areas did not become necrotic and returned to near normal levels after 12 h. No significant change in tumor hypoxia was seen at 90 min or 12 h. For both tumor types, RRx-001 treatment resulted in the loss of perfusion in the large regions of the tumor; however, at the 12-h time point, both tumor types showed an increase in vessel perfusion but no significant decrease in hypoxia.
  
  
  CONCLUSIONS
  These data suggest a redistribution of blood flow within the tumor for both tumor types akin to vascular normalization. Differences between the tumors were related to tumor architecture and distribution of alpha-smooth muscle actin (α-SMA). RRx-001 shows promise for short-term blood flow redistribution in tumors with a pericyte- and α-SMA-rich vasculature. Expression of α-SMA in tumor vasculature could therefore be useful for predicting tumor response to RRx-001.
authors.affiliation: EpicentRx, Inc, 800 W El Camino Real, Suite 180, Mountain View, CA 94040 USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: EpicentRx, Inc, 800 W El Camino Real, Suite 180, Mountain View, CA 94040 USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: Department of Bioengineering, University of California San Diego (UCSD), 9500 Gilman Dr, La Jolla, CA 92093 USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: Cabenda Pharmaceutical Research, 1060 East 10th Ave, Vancouver, BC V5T 2B5 Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Minchinton
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001384:Azetidines / Q000008:administration & dosage* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009574:Nitro Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D001384:Azetidines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009574:Nitro Compounds; D009593:Nitroimidazoles; C577469:RRx-001; C033815:pimonidazole
keywords: Chemosensitizer; Epigenetic agent; RRx-001; Radiosensitizer; Tumor; Vascular normalization