YM-201627: an orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation.

Abstract

We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039-0.12 microM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01 microM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30 mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10 mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.

• Authors: Nobuaki Amino, Yukitaka Ideyama, Mayumi Yamano, Sadao Kuromitsu, Katsunori Tajinda, Kiyohiro Samizu, Akira Matsuhisa, Masafumi Kudoh, Masayuki Shibasaki
• Journal: Cancer letters (Cancer Lett) Vol. 238 Issue 1 Pg. 119-27 (Jul 08 2006) ISSN: 0304-3835 [Print] Ireland
• PMID: 16095812 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inducing Agents
• Antineoplastic Agents
• Imidazoles
• YM-201627
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Administration, Oral
• Angiogenesis Inducing Agents (pharmacology)
• Animals
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Endothelial Cells (drug effects)
• Humans
• Imidazoles (chemistry, therapeutic use)
• Melanoma, Experimental (drug therapy)
• Mice
• Mice, Inbred Strains
• Phosphorylation (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (analysis, drug effects)
• Xenograft Model Antitumor Assays