Adenoviral vectors expressing human endostatin-angiostatin and soluble Tie2: Enhanced suppression of tumor growth and antiangiogenic effects in a prostate tumor model

Sudhanshu P. Raikwar, Constance J. Temm, Nandita S. Raikwar, Chinghai Kao, Bruce A. Molitoris, Thomas A. Gardner

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Angiogenesis is essential for prostate cancer development and metastasis. Antiangiogenic therapy targeting tumor neovasculature, therefore, represents a promising approach for prostate cancer treatment. We hypothesized that adenoviral-mediated delivery of a combination of antiangiogenic factors might have an enhanced antitumor response. We developed the adenoviral vectors Ad-hEndo-angio, expressing a unique, chimeric human endostatin-angiostatin fusion protein, and Ad-sTie2, expressing a soluble form of endothelium-specific receptor tyrosine kinase Tie2. Matrigel angiogenesis assays using Ad-hEndo-angio revealed significant inhibition of tubular network formation and endothelial sprouting compared to Ad-sTie2. In vivo studies in a bilateral PC-3 tumor xenograft model following either intratumoral or systemic administration of Ad-hEndo-angio led to enhanced tumor growth suppression compared to Ad-sTie2. A novel finding is that an intratumoral, combination therapy employing one-half the dose of Ad-hEndo-angio as well as Ad-sTie2 led to a complete regression of the injected, as well as the contralateral uninjected, tumor and prolonged the tumor-free survival in 80% of the animals. In addition, a novel, real-time, intravital imaging modality was used to monitor antiangiogenic responses following adenoviral-mediated gene transfer. These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer.

Original languageEnglish (US)
Pages (from-to)1091-1100
Number of pages10
JournalMolecular Therapy
Volume12
Issue number6
DOIs
StatePublished - Dec 2005

Keywords

  • Angiogenesis
  • Angiostatin
  • Endostatin
  • Intravital imaging
  • Prostate cancer
  • Tie2

ASJC Scopus subject areas

  • Molecular Biology

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