Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Ines Beyer, Hua Cao, Jonas Persson, Hui Song, Maximilian Richter, Qinghua Feng, Roma Yumul, Ruan van Rensburg, Zongyi Li, Ronald Berenson, Darrick Carter, Steve Roffler, Charles Drescher, André Lieber
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 12 Pg. 3340-51 (Jun 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22535153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Desmoglein 2
• Recombinant Proteins
• Viral Proteins

Topics

• Adenoviridae
• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Desmoglein 2 (metabolism)
• Drug Therapy, Combination
• Humans
• Intercellular Junctions (drug effects)
• Mice
• Mice, SCID
• Mice, Transgenic
• Recombinant Proteins (administration & dosage)
• Viral Proteins (administration & dosage)
• Xenograft Model Antitumor Assays