Vascular endothelial growth factor immunoneutralization in combination with cisplatin reduces EAC tumor growth.
In the present study, we evaluated the effects of a neutralizing anti-Vascular Endothelial Growth Factor (VEGF) polyclonal antibody on murine EAC tumor growth both in vitro and in vivo. Furthermore, we investigated if in the presence of effective VEGF blockade, a conventional chemotherapeutic drug Cisplatin could be effective, and if so would there be an additive effect of the combination regimen. An in vitro cell proliferation assay using MTT kit showed that VEGF antibody alone inhibited proliferation of EAC cells significantly in all the three time intervals (p<0.05). But cisplatin treatment in combination with VEGF antibody resulted in highly significant inhibition (p<0.001) of cell proliferation. Apoptosis assay by FACS analysis showed that VEGF antibody-cisplatin combination treatment induced apoptosis in cultured EAC cells. Intraperitoneal administration of VEGF antibody (100 mug/dose) and cisplatin (0.5 mg/kg/dose) combination was observed to be more effective in reducing tumor burden and increasing life span when compared to VEGF antibody or cisplatin treatment alone in EAC solid tumor bearing mice. In EAC ascites tumor model, all the three types of treatment inhibited tumor burden and increased life span, but the inhibition was less compared to EAC solid tumor bearing mice. VEGF antibody singly and in combination with cisplatin reduced neoangiogenesis and vascular hyperpermeability. However, it is clear from the results that the combination treatment had no additive effect in reducing vascular hyperpermeability. Serum VEGF was not reduced significantly after treatment in EAC ascites tumor bearing mice, whereas in EAC solid tumor bearing mice it was reduced significantly after treatment. The results clearly show that though alone cisplatin showed antitumor efficacy but it had no significant inhibitory effect on neoangiogenesis and vascular hyperpermeability. Thus the present study suggests that anti-VEGF agent can be combined with traditional treatment modalities to ensure more effectiveness.
Ghosh
Sonali
S
Department of Metabolic Regulation, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata-700026, India.
Maity
Putul
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000097:blood / Q000276:immunology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000276:immunology*
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D002945:Cisplatin