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

Fengshuo Jin, Zhihui Xie, Calvin J. Kuo, Leland W K Chung, Chia Ling Hsieh

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)257-267
Number of pages11
JournalCancer Gene Therapy
Volume12
Issue number3
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

Fingerprint

Adenoviridae
Endothelium
Prostatic Neoplasms
Osteocalcin
Growth
Human Umbilical Vein Endothelial Cells
Neoplasms
Therapeutics
Cholecalciferol
Stromal Cells
Coculture Techniques
Tumor Burden
Heterografts
Confocal Microscopy
Genetic Therapy
Androgens
Prostate
Endothelial Cells
Epithelial Cells
Hormones

Keywords

  • Antiangiogenesis
  • Oncolytic adenoviruses
  • Prostate cancer
  • Tumor-endothelial interaction
  • VEGF receptor

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy. / Jin, Fengshuo; Xie, Zhihui; Kuo, Calvin J.; Chung, Leland W K; Hsieh, Chia Ling.

In: Cancer Gene Therapy, Vol. 12, No. 3, 03.2005, p. 257-267.

Research output: Contribution to journalArticle

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