title: Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs.
abstract: OBJECTIVE
  Epithelial junctions between tumor cells inhibit the penetration of anticancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3-derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the antitumor effects of several therapeutic monoclonal antibodies. The goal of this study was to evaluate whether JO-1 cotherapy can also improve the efficacy of chemotherapeutic drugs.
  
  
  METHODS
  The effect of intravenous application of JO-1 in combination with several chemotherapy drugs, including paclitaxel/Taxol, nanoparticle albumin-bound paclitaxel/Abraxane, liposomal doxorubicin/Doxil, and irinotecan/Camptosar, was tested in xenograft models for breast, colon, ovarian, gastric and lung cancer. Because JO-1 does not bind to mouse cells, for safety studies with JO-1, we also used human DSG2 (hDSG2) transgenic mice with tumors that overexpressed hDSG2.
  
  
  RESULTS
  JO-1 increased the efficacy of chemotherapeutic drugs, and in several models overcame drug resistance. JO-1 treatment also allowed for the reduction of drug doses required to achieve antitumor effects. Importantly, JO-1 coadmininstration protected normal tissues, including bone marrow and intestinal epithelium, against toxic effects that are normally associated with chemotherapeutic agents. Using the hDSG2-transgenic mouse model, we showed that JO-1 predominantly accumulates in tumors. Except for a mild, transient diarrhea, intravenous injection of JO-1 (2 mg/kg) had no critical side effects on other tissues or hematologic parameters in hDSG2-transgenic mice.
  
  
  CONCLUSIONS
  Our preliminary data suggest that JO-1 cotherapy has the potential to improve the therapeutic outcome of cancer chemotherapy.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Beyer
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.forename: Jonas
authors.initials: J
authors.lastname: Persson
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.forename: Maximilian
authors.initials: M
authors.lastname: Richter
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Feng
authors.forename: Roma
authors.initials: R
authors.lastname: Yumul
authors.forename: Ruan
authors.initials: R
authors.lastname: van Rensburg
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Li
authors.forename: Ronald
authors.initials: R
authors.lastname: Berenson
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.forename: Steve
authors.initials: S
authors.lastname: Roffler
authors.forename: Charles
authors.initials: C
authors.lastname: Drescher
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D051301:Desmoglein 2 / Q000378:metabolism; D004359:Drug Therapy, Combination; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000008:administration & dosage; D014764:Viral Proteins / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051301:Desmoglein 2; D011994:Recombinant Proteins; D014764:Viral Proteins