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

Prostate. 2008 Jul 1;68(10):1105-15. doi: 10.1002/pros.20775.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Cell Division / drug effects
  • Disease Models, Animal
  • Doxorubicin / pharmacology*
  • Drug Therapy, Combination
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Androgens
  • Antibiotics, Antineoplastic
  • Receptors, Androgen
  • Tumor Necrosis Factor-alpha
  • tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse
  • Doxorubicin