Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

Cancer Gene Ther. 2005 Mar;12(3):257-67. doi: 10.1038/sj.cgt.7700790.


Tumor-endothelial interaction contributes to local prostate tumor growth and distant metastasis. In this communication, we designed a novel approach to target both cancer cells and their "crosstalk" with surrounding microvascular endothelium in an experimental hormone refractory human prostate cancer model. We evaluated the in vitro and in vivo synergistic and/or additive effects of a combination of conditional oncolytic adenovirus plus an adenoviral-mediated antiangiogenic therapy. In the in vitro study, we demonstrated that human umbilical vein endothelial cells (HUVEC) and human C4-2 androgen-independent (AI) prostate cancer cells, when infected with an antiangiogenic adenoviral (Ad)-Flk1-Fc vector secreting a soluble form of Flk1, showed dramatically inhibited proliferation, migration and tubular formation of HUVEC endothelial cells. C4-2 cells showed maximal growth inhibition when coinfected with Ad-Flk1-Fc and Ad-hOC-E1, a conditional replication-competent Ad vector with viral replication driven by a human osteocalcin (hOC) promoter targeting both prostate cancer epithelial and stromal cells. Using a three-dimensional (3D) coculture model, we found that targeting C4-2 cells with Ad-hOC-E1 markedly decreased tubular formation in HUVEC, as visualized by confocal microscopy. In a subcutaneous C4-2 tumor xenograft model, tumor volume was decreased by 40-60% in animals treated with Ad-Flk1-Fc or Ad-hOC-E1 plus vitamin D3 alone and by 90% in a combined treatment group, compared to untreated animals in an 8-week treatment period. Moreover, three of 10 (30%) pre-established tumors completely regressed when animals received combination therapy. Cotargeting tumor and tumor endothelium could be a promising gene therapy strategy for the treatment of both localized and metastatic human prostate cancer.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / therapy*
  • Adenoviridae / genetics
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / genetics
  • Angiogenesis Inhibitors / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cholecalciferol / administration & dosage
  • Cholecalciferol / therapeutic use
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Genetic Vectors / therapeutic use
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / therapy*
  • Neovascularization, Pathologic / prevention & control*
  • Osteocalcin / administration & dosage
  • Osteocalcin / genetics
  • Promoter Regions, Genetic / genetics
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / therapy*
  • Tetrazolium Salts
  • Thiazoles
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor Receptor-2 / administration & dosage
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / therapeutic use*


  • Angiogenesis Inhibitors
  • Tetrazolium Salts
  • Thiazoles
  • Osteocalcin
  • Cholecalciferol
  • Vascular Endothelial Growth Factor Receptor-2
  • thiazolyl blue