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Clin Cancer Res. 2012 Jun 15;18(12):3340-51. doi: 10.1158/1078-0432.CCR-11-3213. Epub 2012 Apr 24.

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

Author information

1
Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.

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.

PMID:
22535153
PMCID:
PMC3547677
DOI:
10.1158/1078-0432.CCR-11-3213
[Indexed for MEDLINE]
Free PMC Article

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