The effect of the
antitumor drug MDL 101,731 [(E)-2'-deoxy-2'-(fluoromethylene)
cytidine] on
tumor growth and on steady-state
vascular endothelial 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 quantitative in situ hybridization.
MDL 101,731 caused regression of MDA-MB-231 and PC-3
tumor xenografts, but only inhibition of growth (without regression) of MCF-7 xenografts. The
drug caused inhibition of growth of HT-29 xenografts at low doses, and regression at high doses. When treatment with
MDL 101,731 led to
tumor regression,
VEGF mRNA levels were decreased. When treatment led only to inhibition of growth, there 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 the drop in
VEGF mRNA observed in
tumors from mice treated with
MDL 101,731 correlated with a loss of zones of
necrosis. In contrast, treatment with
cisplatin led to either an increase (PC-3) or no change (MDA-MB-231) in
VEGF mRNA levels, and no loss of necrotic zones. Quantitative analysis of changes in
VEGF mRNA levels was supported by immunohistochemical analysis of
VEGF protein in the same
tumor specimens. In vitro,
MDL 101,731 was a potent inhibitor of
VEGF secretion in cells exposed to
hypoxia, whereas there was no effect of
cisplatin on
VEGF secretion by three of the four cell lines tested. These findings suggest that inhibition of
VEGF expression by
MDL 101,731 may distinguish this compound from other classes of
cytotoxic agents, such as
cisplatin.