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-alpha 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.
Bertilaccio
Maria T S
MT
Cancer Immunotherapy and Gene Therapy Program, Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy.
Grioni
Matteo
M
Sutherland
Brent W
BW
Degl'Innocenti
Elena
E
Freschi
Massimo
M
Jachetti
Elena
E
Greenberg
Norman M
NM
Corti
Angelo
A
Bellone
Matteo
M
D000728:Androgens / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000728:Androgens; D000903:Antibiotics, Antineoplastic; D011944:Receptors, Androgen; D014409:Tumor Necrosis Factor-alpha; C464840:tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse; D004317:Doxorubicin