Effect of inhibition of multiple steps of angiogenesis in syngeneic murine pleural mesothelioma.

Publication Type	Academic Article
Authors	Merritt R, Yamada R, Wasif N, Crystal R, Korst R
Journal	Ann Thorac Surg
Volume	78
Issue	3
Pagination	1042-51; discussion 1042-51
Date Published	09/01/2004
ISSN	1552-6259
Keywords	Angiogenesis Inhibitors, Eye Proteins, Mesothelioma, Nerve Growth Factors, Pleural Neoplasms, Proteins, Serpins
Abstract	BACKGROUND: Angiogenesis is a multistep process in which the endothelial cell plays a pivotal role. We hypothesized that the combination of two antiangiogenic agents with distinct mechanisms of action would more effectively inhibit tumor growth than either agent alone in a murine mesothelioma model. METHODS: A syngeneic murine mesothelioma flank tumor model (AB-12) was established in BALB/c mice. Separate adenovirus vectors expressing the cDNAs for human pigment epithelium-derived factor (AdPEDF) and a soluble form of the human vascular endothelial growth factor receptor-1 (Adsflt-1) were administered intratumorally. End points measured included tumor size, animal survival, and microvessel density using CD31 immunohistochemistry. An orthotopic model of mesothelioma was established by implanting AB-12 cells into the murine pleural cavity. Simultaneously, AdPEDF and Adsflt-1 were instilled intrapleurally and tumor burden and survival were recorded. The development of pulmonary emphysema was also assessed by calculating the mean linear intercept (a measure of interalveolar septal distance) in histologic lung sections from tumor-free mice after vector administration. RESULTS: In the flank tumor model, the combination of AdPEDF and Adsflt-1 inhibited tumor growth, prolonged survival, and decreased microvessel density more profoundly compared with either AdPEDF or Adsflt-1 alone. In the orthotopic model, the combination was also more effective in prolonging survival. Intrapleural AdPEDF or Adsflt-1 did not increase the mean linear intercept compared with controls in tumor-free mice. CONCLUSIONS: In this murine model, inhibiting multiple mechanisms of angiogenesis using two agents is a more effective antineoplastic strategy than using either agent alone. In addition, instillation of antiangiogenic gene transfer vectors into the pleural space does not result in histologic evidence of pulmonary emphysema.
DOI	10.1016/j.athoracsur.2004.03.021
PubMed ID	15337045