DECREASED VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION ASSOCIATED WITH TUMOR-REGRESSION INDUCED BY (E)-2'-DEOXY-2'-(FLUOROMETHYLENE)CYTIDINE (MDL-101,731)

The effect of the antitumor drug MDL 101,731 [(E)-2'-deoxy-2'-(fluorom ethylene)cytidine] on tumor growth and on steady-state vascular endoth elial growth factor (VEGF) mRNA levels in MDA-MB-231, PC-3, MCF-7, and HT-29 human tumor xenografts grown in nude mice was examined, using q uantitative in situ hybridization. MDL 101,731 caused regression of MD A-MB-231 and PC-3 tumor xenografts, but only inhibition of growth (wit hout regression) of MCF-7 xenografts. The drug caused inhibition of gr owth of HT-29 xenografts at low doses, and regression at high doses. W hen treatment with MDL 101,731 led to tumor regression, VEGF mRNA leve ls were decreased. When treatment led only to inhibition of growth, th ere was no significant change in VEGF mRNA. Further examination of the tumor xenografts revealed that elevated VEGF mRNA was associated with hypoxic zones surrounding areas of necrosis in the tumors, and that t he drop in VEGF mRNA observed in tumors from mice treated with MDL 101 ,731 correlated with a loss of zones of necrosis. in contrast, treatme nt with cisplatin led to either an increase (PC-3) or no change (MDA-M B-231) in VEGF mRNA levels, and no loss of necrotic zones. Quantitativ e analysis of changes in VEGF mRNA levels was supported by immunohisto chemical analysis of VEGF protein in the same tumor specimens. In vitr o, MDL 101,731 was a potent inhibitor of VEGF secretion in cells expos ed to hypoxia, whereas there was no effect of cisplatin on VEGF secret ion by three of the four cell lines tested. These findings suggest tha t inhibition of VEGF expression by MDL 101,731 may distinguish this co mpound From other classes of cytotoxic agents, such as cisplatin.