Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer.
Although the systemic administration of a number of different gene products has been shown to result in the inhibition of angiogenesis and tumor growth in different animal tumor models, the relative potency of those gene products has not been studied rigorously. To address this issue, recombinant adenoviruses encoding angiostatin, endostatin, and the ligand-binding ectodomains of the vascular endothelial growth factor receptors Flk1, Flt1, and neuropilin were generated and used to systemically deliver the different gene products in several different preexisting murine tumor models. Single i.v. injections of viruses encoding soluble forms of Flk1 or Flt1 resulted in approximately 80% inhibition of preexisting tumor growth in murine models involving both murine (Lewis lung carcinoma, T241 fibrosarcoma) and human (BxPC3 pancreatic carcinoma) tumors. In contrast, adenoviruses encoding angiostatin, endostatin, or neuropilin were significantly less effective. A strong correlation was observed between the effects of the different viruses on tumor growth and the activity of the viruses in the inhibition of corneal micropocket angiogenesis. These data underscore the need for comparative analyses of different therapeutic approaches that target tumor angiogenesis and provide a rationale for the selection of specific antiangiogenic gene products as lead candidates for use in gene therapy approaches aimed at the treatment of malignant and ocular disorders.
Department of Genetics, Harvard Medical School, Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
C J
CJ
Kuo
F
F
Farnebo
E Y
EY
Yu
R
R
Christofferson
R A
RA
Swearingen
R
R
Carter
H A
HA
von Recum
J
J
Yuan
J
J
Kamihara
E
E
Flynn
R
R
D'Amato
J
J
Folkman
R C
RC
Mulligan
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000235:genetics; D005069:Evaluation Studies as Topic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D014162:Transfection; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1