Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

• Published in: Clinical cancer research Vol. 14; no. 3; pp. 939 - 949
• Main Authors: KE XIA CAI, LAI YING TSE, LEUNG, Carly, TARN, Paul K. H, RUIAN XU, MAI HAR SHAM
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2008
• Subjects: adeno-associated virus; Adeno-associated virus 2; Adenocarcinoma - pathology; Angiogenesis Inhibitors - pharmacology; Animals; antiangiogenesis inhibitor; Antineoplastic agents; Biological and medical sciences; Calreticulin - genetics; Calreticulin - pharmacology; Cell Division - drug effects; Cloning, Molecular; Dependovirus - physiology; gene therapy; Humans; Lung Neoplasms - pathology; lung tumor; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Metastasis - prevention & control; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Pneumology; Recombinant Proteins - pharmacology; Tumors of the respiratory system and mediastinum; vasostatin; Lung disease; Respiratory disease; Lung cancer; Rodentia; Metastasis; Malignant tumor; Dependovirus; Gene expression; Bronchopulmonary; Virus; Vertebrata; Mammalia; Tumor growth; Mouse; Parvoviridae; Animal; Bronchus disease; Cancer; Parvovirinae
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1930

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.