Anti-tumor activity of the novel angiogenesis inhibitor anginex.
Anginex is a novel cytokine-like peptide with potent anti-angiogenic activity, which operates specifically against angiogenically-activated endothelial cells via prevention of cell adhesion/migration on the extracellular matrix and subsequent induction of apoptosis. Here, we demonstrate that anginex inhibits tumor growth in vivo in mouse xenograft models. In the MA148 ovarian carcinoma model, tumor growth was inhibited dose-dependently by up to 80% when systemically administered via osmotic mini-pumps starting at the time of tumor cell inoculation. The optimal dose was found to be 10 mg/kg per day. When tested against established tumors, mini-pump-administered anginex demonstrated essentially the same effectivity at this optimal dose, whereas once or twice-daily injections were only half as effective. When anginex was conjugated to human serum albumin, effectivity was significantly improved, most likely due to increased bioavailability of the conjugate. Immunohistochemical analysis of microvessel density indicated that the anti-tumor activity of anginex is mediated by angiogenesis inhibition. This was confirmed in an in vitro angiogenesis assay based on tube formation in a collagen gel. Animals demonstrated no signs of toxicity as judged by unaltered behavior, normal weight gain, blood markers and macro- and microscopic morphology of internal organs upon autopsy. Overall, these in vivo studies indicate that anginex is an effective anti-tumor agent.
Dings
Ruud P M
RP
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Health Sciences Center, 321 Church Street, Minneapolis, MN 55455, USA.
van der Schaft
Daisy W J
DW
Hargittai
Balazs
B
Haseman
Judy
J
Griffioen
Arjan W
AW
Mayo
Kevin H
KH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007260:Infusion Pumps; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009995:Osmosis; D010455:Peptides; D011506:Proteins / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010455:Peptides; D011506:Proteins; D012709:Serum Albumin; C111993:betapep-25 protein, synthetic