Non-peptide small molecule regulators of lymphangiogenesis.
Adrenomedullin (AM) and gastrin releasing peptide (GRP) are neuroendocrine peptides that have been previously implicated as regulators of angiogenesis and lymphangiogenesis. Using an immortalized human dermal microvascular lymphatic endothelial cell line stably transfected with red fluorescent protein (LEC/RFP), we demonstrate the ability of AM and GRP to augment tube formation complexity of this target cell in a dose-dependent manner. Maximum tube density was initiated at 1 nM for both peptides, and as concentrations exceeded 10 nM a decrease in tube formation was noted, hence following a classic rise/fall biological response curve. In addition, we show that appropriate small molecule mimetics to neutralizing monoclonal antibodies of AM or GRP, at 1 microM concentration, can function to either inhibit (antagonist) or enhance (super agonist) peptide-induced tube formation of LEC/RFP. Our small molecule reagents by themselves have no activity, but in the presence of their respective peptides can mediate a positive or negative response, hence the super agonist designation. These compounds represent new regulatory drugs of the lymphatic system with possible patient application in the clinical management of edema and metastatic disease.
NCI Angiogenesis Core Facility, National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Advanced Technology Center, Bethesda, Maryland 20892-4605, USA.
Changge
C
Fang
Marta Aparicio
MA
Miguel
Ingalill
I
Avis
Alfredo
A
Martinez
Enrique
E
Zudaire
Frank
F
Cuttitta
D053607:Adrenomedullin / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019886:Gastrin-Releasing Peptide / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D054852:Small Molecule Libraries
D000911:Antibodies, Monoclonal; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D053607:Adrenomedullin; D019886:Gastrin-Releasing Peptide