The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice

Authors

  • Rébécca Phaeton MD,

    1. Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine, Albert Einstein Cancer Center, Bronx, New York
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  • Xing Guo Wang PhD,

    1. Faculty of Life Sciences, Hubei University, Wuhan, China
    2. Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York
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  • Mark H. Einstein MD,

    1. Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine, Albert Einstein Cancer Center, Bronx, New York
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  • Gary L. Goldberg MD,

    1. Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine, Albert Einstein Cancer Center, Bronx, New York
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  • Arturo Casadevall MD, PhD,

    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York
    2. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
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  • Ekaterina Dadachova PhD

    Corresponding author
    1. Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York
    2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York
    • Department of Nuclear Medicine, Albert Einstein College of Medicine, 1695A Eastchester Road, Bronx, NY 10461
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    • Fax: (718) 405-8457


  • The articles in this supplement were presented at the “12th Conference on Cancer Therapy with Antibodies and Immunoconjugates,” Parsippany, New Jersey, October 16-18, 2008.

Abstract

BACKGROUND:

Human papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer, and >95% of all cervical cancers have detectable HPV sequences. The authors of this report recently demonstrated the efficacy of radioimmunotherapy (RIT) targeting viral oncoprotein E6 in the treatment of experimental cervical cancer. They hypothesized that the pretreatment of tumor cells with various agents that cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors.

METHODS:

HPV type 16 (HPV-16)-positive CasKi cells were treated in vitro with up to 6 grays of external radiation, or with the proteasome inhibitor MG-132, or with unlabeled anti-E6 antibody C1P5; and cell death was assessed. The biodistribution of 188Re-labeled C1P5 antibody was determined in both control and radiation MG-132-treated CasKi tumor-bearing nude mice.

RESULTS:

188Re-C1P5 antibody demonstrated tumor specificity, very low uptake, and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pretreatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by the authors' previous in vivo studies in a CasKi tumor model.

CONCLUSIONS:

The current results indicated that pretreatment of cervical tumors with the proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate nonviable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor the further development of RIT for cervical cancers targeting viral antigens. Cancer 2010;116(4 suppl):1067–74. © 2010 American Cancer Society.

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