Vasculature-targeted tumor necrosis factor-alpha increases the therapeutic index of doxorubicin against prostate cancer

Authors

  • Maria T.S. Bertilaccio,

    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
    2. Univeristà Vita-Salute San Raffaele, Milan, Italy
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  • Matteo Grioni,

    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
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  • Brent W. Sutherland,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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  • Elena Degl'Innocenti,

    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
    Current affiliation:
    1. 4-Antibody AG, Schwarzwaldallee 215 CH-4002, Basel, Switzerland.
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  • Massimo Freschi,

    1. Unità Operativa Anatomia Patologica, Istituto Scientifico San Raffaele, Milan, Italy
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  • Elena Jachetti,

    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
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  • Norman M. Greenberg,

    1. Univeristà Vita-Salute San Raffaele, Milan, Italy
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  • Angelo Corti,

    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
    2. IIT Network Research Unit of Molecular Neuroscience, Istituto Scientifico San Raffaele, Milan, Italy
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  • Matteo Bellone

    Corresponding author
    1. Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy
    • Cellular Immunology Unit, 3P-A1, Dibit, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
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Abstract

BACKGROUND

Poor penetration and uneven distribution of doxorubicin in tumors limits the efficacy of this drug in patients with prostate cancer (PC). Aim of the study was to investigate whether pre-treatment with NGR-TNF, a tumor necrosis factor-α derivative able to target tumor vessels and alter vessel permeability, increases the penetration and the efficacy of doxorubicin in pre-clinical models of PC.

METHODS

Wild type C57BL/6 mice bearing androgen-independent TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develop PC and metastasis, were treated with repeated cycles of doxorubicin, administered either alone or following NGR-TNF. Tumor growth and drug uptake by cancer cells was evaluated.

RESULTS

Doxorubicin as a single agent blocked the growth of TRAMP-C1 cells in vitro but not in vivo. Pre-treatment of mice bearing subcutaneous TRAMP-C1 tumors with NGR-TNF favored doxorubicin penetration into the tumor mass, and in both TRAMP-C1 and TRAMP models significantly delayed tumor growth without increasing drug-related toxicity.

CONCLUSIONS

Pre-treatment with NGR-TNF significantly expanded the therapeutic index of doxorubicin in mouse models of hormone-dependent and -independent PC. Prostate 68:1105–1115, 2008. © 2008 Wiley-Liss, Inc.

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