Inhibition of ornithine decarboxylase (ODC) decreases tumor vascularization and reverses spontaneous tumors in ODC/Ras transgenic mice.
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 alpha-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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The Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Trempus
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Gilmour
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras / Q000235:genetics*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000517:prevention & control; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D019076:Transgenes
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; D009955:Ornithine Decarboxylase; D000518:Eflornithine