With rapid growth and metabolism, aggressive cancers require an extensive vascular network, termed tumor angiogenesis. The body produces a variety of natural angiogenic inhibitors, among which is the mammalian estrogen metabolite, 2-methoxyestradiol (2-MeOE2). In this study, we compared the effects of 2-MeOE2 on a human umbilical vein cell line (HUVEC-C) and on an immortal, angiotumor-producing rat sinusoidal endothelial cell line (RSE-1). In vitro, the effects of varying concentrations of 2-MeOE2 from 0.01-100.0 microM were measured with cell counts and compared to control cells. HUVEC-C had an ED50 approximately 3.5 microM with approximately 27% inhibition of cell growth whereas RSE-1 had an ED50 approximately 2.2 microM with approximately 50% inhibition of cell growth compared with controls. The lowest concentration with maximal effect was 10.0 microM 2-MeOE2 for both cell lines. Using this concentration, flow cytometric analysis of cell cycles was performed with propidium iodide stained DNA of HUVEC-C and RSE-1 at 24 and 48 hr. Both demonstrated a significant (P < 0.0001) block at G2M of the cell cycle. At 48 hr, HUVEC-C had 32% of cells in G2M (control = 9% G2M), and RSE-1 had 36% of cells in G2M (control = 18% G2M). These findings demonstrate a strong in vitro antiproliferative effect of 2-MeOE2 on normal dividing endothelial as well as angiotumor cells mediated through a cell cycle-specific block at G2M. The antiendothelial, antiangiotumor effect of 2-MeOE2 supports its potential as a therapeutic agent against solid organ cancers, benign or malignant vascular growths, and other pathologic states dependent on angiogenesis.

EVOLUTION OF THE 2020 INTERNATIONAL SOCIETY OF LYMPHOLOGY CONSENSUS DOCUMENT PARALLELS ADVANCES IN LYMPHOLOGY: AN HISTORICAL PERSPECTIVE