Inhibition of breast cancer in nude mouse model by anti-angiogenesis.
The mechanism by which DL-alpha-difluoromethylornithine (DFMO) inhibits angiogenesis is generally thought to involve the inhibition of the rate-limiting enzyme, ornithine decarboxylase (ODC), leading to polyamine depletion in cells and the ultimate cytostatic effect on proliferating endothelial cells. Another mechanism for inhibiting tumor growth involves pentosan polysulfate (PPS) which binds heparin-binding growth factors, known to be crucial for tumor angiogenesis. To quantitate the combined anti-angiogenic effect of DFMO and PPS on tumors, blood vessels were stained using monoclonal antibodies against the platelet endothelial cell adhesion molecule (PECAM). When compared to untreated mice, DFMO/PPS-treated mice exhibited significantly lower (6-fold) blood vessel counts. Furthermore, mice receiving the combination drug treatment had prolonged life compared to untreated tumor-bearing mice, but less than normal tumor-free mice. The prolonged life span of drug treated tumor-bearing mice also correlated with reduced tumor burden in these mice. The use of single drug treatment results in rapid tumor growth and eventual death of tumor-bearing mice. We have demonstrated that there was significant difference in survival time which correlated to less tumor burden in treated groups of mice as compared to the controls. Inhibition of tumor angiogenesis by the drug combinations suggest that these compounds are anti-angiogenic agents for potential use in clinical trial.
Vincent T. Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
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D000818:Animals; D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D000518:Eflornithine / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010426:Pentosan Sulfuric Polyester / Q000627:therapeutic use* / Q000633:toxicity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010426:Pentosan Sulfuric Polyester; D000518:Eflornithine