Effect of inhibition of multiple steps of angiogenesis in syngeneic murine pleural mesothelioma.
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.
Merritt
Robert E
RE
Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.
Yamada
Reiko E
RE
Wasif
Nabil
N
Crystal
Ronald G
RG
Korst
Robert J
RJ
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004359:Drug Therapy, Combination; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins / Q000008:administration & dosage*; D018014:Gene Transfer Techniques; D008297:Male; D008654:Mesothelioma / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018995:Myosin Heavy Chains; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D024501:Nonmuscle Myosin Type IIB; D010997:Pleural Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D011506:Proteins / Q000008:administration & dosage*; D015843:Serpins / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000099174:Pigment Epithelium-Derived Factor
D020533:Angiogenesis Inhibitors; D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D018995:Myosin Heavy Chains; D009414:Nerve Growth Factors; D024501:Nonmuscle Myosin Type IIB; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C103815:nonmuscle myosin type IIB heavy chain