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 g rowth/metastasis using an angiogenesis-inhibitory drug. Two cloned tum or cell lines designated OV-LM and OV-HM were isolated from a murine o varian carcinoma OV2944. OV-LM and OV-HM cells grew in cultures at com parable rates. However, when transplanted s.c. into syngeneic mice, OV -HM exhibited a faster growth rate and a much higher incidence of meta stasis to lymph nodes and lung. Histologically, intense neovasculariza tion was detected in sections of OV-HM but not of OV-LM tumor. OV-HM a nd OV-LM tumor cells obtained from in vitro cultures expressed high an d low levels of VEGF mRNA, respectively. A difference in VEGF mRNA exp ression was much more clearly observed between RNAs prepared from fres h OV-HM and OV-LM tumor masses: RNA from OV-HM contained larger amount s 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. Intraperito neal 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 comparab le 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 correla tes with their VEGF-producing capacity and that an angiogenesis inhibi tor, FR118487, inhibits tumor growth and metastasis through mechanism( s) including the suppression of VEGF function in vivo.