Growth reduction of a xenotransplanted human soft tissue sarcoma by MDM2 antisense therapy via implanted osmotic minipumps

  • Authors:
    • Peter Wurl
    • Frank Bartel
    • Axel Meye
    • Matthias Kappler
    • Matthias Bache
    • Hannelore Schmidt
    • Manfred Schonfelder
    • Helge Taubert
  • View Affiliations

  • Published online on: May 1, 2002     https://doi.org/10.3892/ijo.20.5.1087
  • Pages: 1087-1093
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Abstract

The MDM2 oncogene plays an important role in tumorigenesis and especially in soft tissue sarcomas (STS). Overexpression of the MDM2 protein is associated with a poorer prognosis for STS patients. An MDM2 antisense approach to reduce MDM2 protein levels has been successfully applied on several carcinomas in vitro and used on a few in vivo cases. However, antisense treatment not only resulted in an MDM2 protein reduction but also in a wild-type P53 gene (wt-P53) mediated tumor growth suppression due to its genetic wt-P53 status. In this study, we used a clinically relevant xenotransplanted STS model with a mutated P53 gene (mt-P53) in order to exclude the influence of wt-P53. The human STSs were surgically implanted and one week later osmotic pumps were implanted intraperitoneally into nude rats releasing MDM2-antisense ODNs (AS ODNs) continuously for one week. As controls MDM2-sense ODN (SE ODN) or a 0.9% NaCl solution (saline solution) were administered. After one week animals treated with MDM2-AS ODN (100 or 200 μg) showed a reduction in tumor mass in comparison to animals treated with MDM2-SE ODN. The reduction in tumor mass was significant in animals treated with MDM2-AS ODNs in comparison to the saline solution treated ones (p=0.018 or p=0.007). Furthermore, a significant reduction in macroscopically visible tumor number with MDM2-AS ODN treatments (100 or 200 μg) in comparison to MDM2-SE ODN or saline solution treatment (both p=0.009) was observed for the first time. As expected a reduction in MDM2 protein expression in the MDM2-AS ODN treated tumors when compared to the MDM2-SE ODN or saline solution treated tumors was detected in Western blot analyses and immunohistochemically. In addition, an unexpected reduction in mt-P53 protein expression after AS ODN therapy was also observed. In short, we have demonstrated in vivo for the first time that MDM2-AS ODN treatment of xenotransplanted STS (mt-P53) reduces tumor mass, tumor number, MDM2 protein and mt-P53 protein expression. Our findings support the hypothesis that MDM2-AS ODN treatment may exert a tumor inhibiting effect on all MDM2 expressing tumors regardless of the P53-status, this in turn may be of general importance in gene therapy of cancer.

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May 2002
Volume 20 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Wurl P, Bartel F, Meye A, Kappler M, Bache M, Schmidt H, Schonfelder M and Taubert H: Growth reduction of a xenotransplanted human soft tissue sarcoma by MDM2 antisense therapy via implanted osmotic minipumps. Int J Oncol 20: 1087-1093, 2002
APA
Wurl, P., Bartel, F., Meye, A., Kappler, M., Bache, M., Schmidt, H. ... Taubert, H. (2002). Growth reduction of a xenotransplanted human soft tissue sarcoma by MDM2 antisense therapy via implanted osmotic minipumps. International Journal of Oncology, 20, 1087-1093. https://doi.org/10.3892/ijo.20.5.1087
MLA
Wurl, P., Bartel, F., Meye, A., Kappler, M., Bache, M., Schmidt, H., Schonfelder, M., Taubert, H."Growth reduction of a xenotransplanted human soft tissue sarcoma by MDM2 antisense therapy via implanted osmotic minipumps". International Journal of Oncology 20.5 (2002): 1087-1093.
Chicago
Wurl, P., Bartel, F., Meye, A., Kappler, M., Bache, M., Schmidt, H., Schonfelder, M., Taubert, H."Growth reduction of a xenotransplanted human soft tissue sarcoma by MDM2 antisense therapy via implanted osmotic minipumps". International Journal of Oncology 20, no. 5 (2002): 1087-1093. https://doi.org/10.3892/ijo.20.5.1087