Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interfering with vascular endothelial growth factor activity.
The present study investigates the relationship between in vivo growth/metastasis of tumor cells and their capacity to produce the vascular endothelial growth factor (VEGF), as well as the regulation of tumor growth/metastasis using an angiogenesis-inhibitory drug. Two cloned tumor cell lines designated OV-LM and OV-HM were isolated from a murine ovarian carcinoma OV2944. OV-LM and OV-HM cells grew in cultures at comparable rates. However, when transplanted s.c. into syngeneic mice, OV-HM exhibited a faster growth rate and a much higher incidence of metastasis to lymph nodes and lung. Histologically, intense neovascularization was detected in sections of OV-HM but not of OV-LM tumor. OV-HM and OV-LM tumor cells obtained from in vitro cultures expressed high and low levels of VEGF mRNA, respectively. A difference in VEGF mRNA expression was much more clearly observed between RNAs prepared from fresh OV-HM and OV-LM tumor masses: RNA from OV-HM contained larger amounts of VEGF mRNA, whereas RNA from OV-LM exhibited only marginal levels of VEGF mRNA. An angiogenesis-inhibitory drug, FR118487 inhibited the VEGF-mediated in vitro growth of endothelial cells but did not affect the expression in vitro of VEGF mRNA by OV-HM tumor cells. Intraperitoneal injections of FR118487 into mice bearing OV-HM tumors resulted in: (i) a subsequent growth inhibition of primary tumors; (ii) a marked decrease in neovascularization inside tumor masses expressing comparable levels of VEGF mRNA to those detected in control OV-HM masses; and (iii) almost complete inhibition of metastasis to lymph nodes and lung. These results indicate that growth/metastasis of tumor cells correlates with their VEGF-producing capacity and that an angiogenesis inhibitor, FR118487, inhibits tumor growth and metastasis through mechanism(s) including the suppression of VEGF function in vivo.
Mu
J
J
Biomedical Research Center, Osaka University Medical School, Suita.
Abe
Y
Y
Tsutsui
T
T
Yamamoto
N
N
Tai
X G
XG
Niwa
O
O
Tsujimura
T
T
Sato
B
B
Terano
H
H
Fujiwara
H
H
Hamaoka
T
T
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; C096036:FR 118487; D008222:Lymphokines; D012333:RNA, Messenger; D013141:Spiro Compounds; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors