VEGF-DT385 toxin conjugate inhibits mammary adenocarcinoma development in a transgenic mouse model of spontaneous tumorigenesis.
Previous experiments have shown that a vascular endothelial growth factor (VEGF)-DT385 toxin conjugate inhibits endothelial cell proliferation, angiogenesis and solid tumor growth in a xenotransplant model system. Here, we report that VEGF-DT385 toxin conjugate effectively inhibits spontaneous tumorigenesis. The C3(1)/SV40 TAg transgenic mouse model of mammary gland carcinogenesis was used to determine the effectiveness of VEGF-DT385 toxin conjugate in delaying the onset of disease and the development of solid tumors. Animals were treated daily with conjugate for a period of 7 days. Therapy was initiated at week 14 of development before any visible adenocarcinomas were evident. Treatment of mice with VEGF-DT385 toxin conjugate significantly delayed the onset of tumorigenesis and inhibited solid tumor growth by more than 92%. Furthermore, conjugate treated animals showed less than twice the number of tumor nodules when compared to control mice. Finally, this vascular targeting agent significantly increased survival time of animals by 5 weeks. VEGF-DT385 toxin conjugate resulted in temporary weight loss and no long-lasting toxicity was seen. More importantly, using this established tumor model, VEGF-DT385 toxin conjugate appeared to be as effective as a similar treatment schedule with recombinant human endostatin. Our results suggest that VEGF-DT385 toxin conjugate is a potent inhibitor of mammary adenocarcinoma growth and might be useful in breast cancer therapy.
Wild
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Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Yokoyama
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Y
Dings
R P M
RP
Ramakrishnan
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D000230:Adenocarcinoma / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004195:Disease Models, Animal; D043169:Endostatins / Q000494:pharmacology; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D004167:Diphtheria Toxin; D043169:Endostatins; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A