VEGF-DT385 toxin conjugate inhibits mammary adenocarcinoma development in a transgenic mouse model of spontaneous tumorigenesis

R. Wild, Y. Yokoyama, R. P.M. Dings, Sundaram Ramakrishnan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)161-171
Number of pages11
JournalBreast Cancer Research and Treatment
Volume85
Issue number2
DOIs
StatePublished - May 2004

Bibliographical note

Funding Information:
This work was supported in part by, grants from NIH CA 71803, DAMD 17-99-1-9564 from USARMY, Sparboe and Women’s Health Fund Endowment (to S.R.) and a doctoral dissertation fellowship from the University of Minnesota Graduate School (to R.W.). We thank Dr Jeffrey E. Green (National Cancer Institute, NIH, Bethesda, MD) for providing the C3(1)/SV40 TAg transgenic mice. In addition, we thank Dr Roland Gunther (Division of Comparative Medicine, Department of Research Animal Resources, University of Minnesota, Minneapolis, MN) for histologic examination of tissues.

Keywords

  • Angiogenesis
  • Endostatin
  • Mammary carcinoma
  • Tumorigenesis
  • VEGF-DT385 toxin
  • Vascular targeting

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