title: Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Ke Xia
authors.initials: KX
authors.lastname: Cai
authors.forename: Lai Ying
authors.initials: LY
authors.lastname: Tse
authors.forename: Carly
authors.initials: C
authors.lastname: Leung
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.forename: Ruian
authors.initials: R
authors.lastname: Xu
authors.forename: Mai Har
authors.initials: MH
authors.lastname: Sham
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D037282:Calreticulin / Q000235:genetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D003001:Cloning, Molecular; D000229:Dependovirus / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D037282:Calreticulin; D010446:Peptide Fragments; D011994:Recombinant Proteins; C121986:vasostatin