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Carcinogenesis |
The Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096 [L. L., S. K. G.], and Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [C. T.]
We have shown that ornithine decarboxylase (ODC) overexpression in the
skin of TG.AC v-Ha-ras transgenic mice induces the
formation of spontaneous skin carcinomas. Treatment of ODC/Ras double
transgenic mice with 
-difluoromethylornithine (DFMO), a specific
inhibitor of ODC enzyme activity, causes a rapid regression of these
spontaneous tumors. DFMO treatment led to dramatic decreases in ODC
activity and putrescine levels, but v-Ha-ras expression
was not affected in the regressed tumors. Moreover, cyclin D1 continued
to be strongly expressed in the basal epithelial cells of regressed
tumors, and there was no decrease in the proliferative index of these
same tumor cells. Terminal deoxynucleotidyl transferase-mediated
dUTP-biotin nick end labeling analyses revealed increased DNA
fragmentation in DFMO regressed tumors compared with similarly sized
spontaneous tumors from ODC/Ras transgenic mice not treated with DFMO.
Moreover, the blood vessel count was significantly decreased in
regressed tumors within the first four days of DFMO treatment.
The decreased vasculature in DFMO regressed tumors was not attributable
to altered expression of murine vascular endothelial growth factor
(VEGF) isoforms. Elevated levels of ODC activity in the skin of K6/ODC
transgenic mice increased the dermal vascularization compared with that
in nontransgenic normal littermates. Our results suggest that ODC
stimulates an angiogenic factor(s) other than VEGF and/or may play a
key role in a cell survival effector pathway of Ras that is independent
of a Ras-induced proliferation pathway.
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