Prophylactic naked DNA vaccination with the human vascular endothelial growth factor induces an anti-tumor response in C57Bl/6 mice.
Passive immunotherapy against soluble pro-angiogenic factors and/or their receptors in endothelial cells has become a promising approach in cancer therapeutics. There is also experimental evidence indicating that an active immunotherapy strategy directed towards these target molecules could also be effective. In this paper we show that it is possible to reduce tumor growth or increase the survival of tumor-bearing C57Bl/6 mice when animals are vaccinated with the human vascular endothelial growth factor (VEGF) isoform 121 gene (hVEGF(121)), and later challenged with melanoma or lung carcinoma tumor cells. Immunization was done with 10 microg DNA doses of the hVEGF121 gene, which is highly homologous to its mouse counterpart, administered on a weekly basis using a plasmid bearing 5 CpG bacterial motifs. Histopathology analyses of tumors of hVEGF(121) immunized animals showed a decrease in tumor cell density around vessels and in mitotic figures, as well as an increase in apoptotic tumor cells. A statistically significant cell cytotoxic response was found when spleen cells of immunized mice were co-cultured in vitro with mouse tumor VEGF-producing cells. Vaccination with an hVEGF121 gene mutated to make it deficient for VEGF receptor binding, produced similar in vitro and in vivo results, and significantly reduced the number of spontaneous metastases produced by the mouse Lewis lung carcinoma. Our results indicate that human VEGF DNA can be employed for anti-angiogenic active immunotherapy in mice, and that direct cell cytotoxicity is a contributor mechanism to the overall anti-tumor effects seen in immunized animals.
Bequet-Romero
Mónica
M
Recombinant Antibodies Laboratory, Cancer Research Department, Center for Genetic Engineering and Biotechnology, Cubanacán, Playa, P.O. Box 6162, Havana 10600, Cuba. monica.bequet@cigb.edu.cu
Ayala
Marta
M
Acevedo
Boris E
BE
Rodríguez
Ernesto Galbán
EG
Ocejo
Omar López
OL
Torrens
Isis
I
Gavilondo
Jorge V
JV
D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D019496:Cancer Vaccines; D019444:Vaccines, DNA; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma; D040262:Receptors, Vascular Endothelial Growth Factor