TNP-470 and recombinant human interferon-alpha2a inhibit angiogenesis synergistically.
The hypothesis that the combination of two known antiangiogenic agents TNP-470 and interferon (IFN)-alpha exerts synergistic effects has been investigated in vitro and in vivo. In vitro, TNP-470 and recombinant human IFN-alpha2a (rhIFN-alpha2a) resulted in a dose-dependent inhibition of proliferation of human umbilical vein endothelial cells (HUVECs) and EA.hy926 endothelial cells. Compared with the two agents used singly at their lowest or ineffective doses, combined treatment with the same doses inhibited more intensely in the absence of cytotoxicity and displayed similar behaviour on cell chemotaxis and capillary morphogenesis on Matrigel. However, the secretion of matrix metalloproteinase 2 (MMP-2) and MMP-9 was not influenced by the two agents, either alone or in combination, even when they were applied at their lowest efficacious doses or at higher cytotoxic doses. Experiments in vivo with the chick embryo chorioallantoic membrane (CAM)-sponge assay revealed the same dose-dependent inhibition and synergy. As the basic fibroblast growth factor (bFGF)-induced angiogenesis in the CAM-sponge model was strongly inhibited by the combined treatment, TNP-470 and rhIFN-alpha2a would appear to exert antiangiogenesis synergistically, perhaps by interfering with the bFGF-mediated pathway.
Department of Biomedical Sciences and Human Oncology, Institute of Human Anatomy, Histology and Embryology, University of Bari Medical School, Bari, Italy.
M
M
Minischetti
A
A
Vacca
D
D
Ribatti
M
M
Iurlaro
R
R
Ria
A
A
Pellegrino
G
G
Gasparini
A F
AF
Dammacco
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D046508:Culture Techniques; D003510:Cyclohexanes; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects*; D005321:Extraembryonic Membranes / Q000098:blood supply / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011994:Recombinant Proteins; D012717:Sesquiterpenes / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D016222:Fibroblast Growth Factor 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077609:O-(Chloroacetylcarbamoyl)fumagillol