Inhibition of human angiogenesis with heparin and hydrocortisone.
Angiogenesis is a critical determinant of tumor growth and the development of metastases. Heparin, steroids, and heparin/steroid combinations have been used in a variety of in vitro models and in vivo in animal models as effective inhibitors of angiogenesis. We tested heparin, steroid and heparin/steroid combinations at a variety of concentrations to determine their effect on the human 'angiogenic switch' from a resting to a proliferative endothelium in vessels from three placentas (initiation), and the effect of these compounds on the subsequent growth of a human angiogenic response (promotion). Using full-thickness human placental vein discs cultured in three-dimensional fibrin-thrombin clots, we demonstrated that heparin (300, 3000 micrograms/ml), steroid (350, 3500 micrograms/ml), and combinations of heparin/steroid at these doses effectively blocked both initiation and promotion of a human angiogenic response in a dose-dependent fashion. We also demonstrated that high-dose steroid or heparin/steroid treatment for 15 days resulted in disruption of vessel integrity, while treatment with heparin alone produced a suppressed growth rate but had intact vessel architecture. High-dose heparin/steroid treatment could also disrupt a developed angiogenic response and retard further development of an angiogenic response following the cessation of treatment.
Jung
S P
SP
Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Siegrist
B
B
Wade
M R
MR
Anthony
C T
CT
Woltering
E A
EA
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009924:Organ Culture Techniques; D010920:Placenta / Q000098:blood supply; D011247:Pregnancy; D014680:Veins / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D006493:Heparin; D006854:Hydrocortisone