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 microg) 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 microg) 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.