Antineoplastic effects of chemotherapeutic agents are potentiated by NM-3, an inhibitor of angiogenesis.
Antiangiogenic therapy, although effective in shrinking tumors, has not yet been established as a standalone treatment for cancer. This therapeutic limitation can be overcome by combining angiogenesis inhibitors with chemotherapeutic agents. NM-3, a small molecule isocoumarin, is a recently discovered angiogenesis inhibitor. Here we demonstrate that NM-3 inhibits the proliferation of human umbilical vein endothelial cells in vitro, at concentrations 10-fold less than those required to inhibit normal fibroblasts or tumor cells (HT29, MKN28, and MCF-7). NM-3 alone inhibits endothelial sprouting and tube formation in vitro. The results also show that synergistic antiproliferative activity is observed when human umbilical vein endothelial cells are treated with NM-3 in combination with 5-fluorouracil. The effects of treatment with NM-3 and various chemotherapeutic agents were also evaluated in tumor xenografts. The results demonstrate that combined treatment with NM-3 and chemotherapeutic agents significantly reduced mean tumor volume compared with either treatment alone, with no effects on body weight changes. Taken together, these findings demonstrate that NM-3 is a well-tolerated angiogenesis inhibitor that significantly increases the efficacy of existing antineoplastic agents.
Reimer
Corinne L
CL
ILEX Oncology, Inc., 20 Overland Street, Boston, MA 02215, USA.
Agata
Naoki
N
Tammam
Jennifer G
JG
Bamberg
Michael
M
Dickerson
William M
WM
Kamphaus
George D
GD
Rook
Susan L
SL
Milhollen
Michael
M
Fram
Robert
R
Kalluri
Raghu
R
Kufe
Donald
D
Kharbanda
Surender
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D049934:Isocoumarins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003374:Coumarins; D006131:Growth Inhibitors; D049934:Isocoumarins; C453300:isocoumarin NM-3; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil