Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin

Clin Cancer Res. 2008 Feb 1;14(3):939-49. doi: 10.1158/1078-0432.CCR-07-1930.

Abstract

Purpose: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment.

Experimental design: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models--subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models.

Results: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed >50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days.

Conclusion: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.

MeSH terms

  • Adenocarcinoma / pathology*
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Calreticulin / genetics
  • Calreticulin / pharmacology*
  • Cell Division / drug effects*
  • Cloning, Molecular
  • Dependovirus / physiology*
  • Humans
  • Lung Neoplasms / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Metastasis / prevention & control*
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology*
  • Recombinant Proteins / pharmacology

Substances

  • Angiogenesis Inhibitors
  • Calreticulin
  • Peptide Fragments
  • Recombinant Proteins
  • vasostatin