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

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 ves...

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Published in:The Prostate 2008-07, Vol.68 (10), p.1105-1115
Main Authors: Bertilaccio, Maria T.S., Grioni, Matteo, Sutherland, Brent W., Degl'Innocenti, Elena, Freschi, Massimo, Jachetti, Elena, Greenberg, Norman M., Corti, Angelo, Bellone, Matteo
Format: Article
Language:English
Subjects:
androgen-independent
Androgens - metabolism
Animals
Antibiotics, Antineoplastic - pharmacology
CD13
Cell Division - drug effects
chemotherapy
cytokines
Disease Models, Animal
Doxorubicin - pharmacology
Drug Therapy, Combination
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
mouse model
Neovascularization, Pathologic - drug therapy
Neovascularization, Pathologic - pathology
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Receptors, Androgen - metabolism
TRAMP
Tumor Necrosis Factor-alpha - pharmacology
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Summary: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.
ISSN:0270-4137
1097-0045
DOI:10.1002/pros.20775