YB-1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma

Regina Holzmüller, Klaus Mantwill, Cornelia Haczek, Emanuel Rognoni, Martina Anton, Atsuko Kasajima, Wilko Weichert, Denise Treue, Hermann Lage, Tibor Schuster, Jürgen Schlegel, Bernd Gänsbacher, Per S. Holm

研究成果: Article査読

22 被引用数 (Scopus)

抄録

The human Y-box binding protein 1 (YB-1) is known to be a promising target for cancer therapy. We have demonstrated that YB-1 plays an important role in the adenoviral life cycle by regulating the adenoviral E2-gene expression. Thus, we studied the oncolytic effect of the recombinant adenovirus Ad-Delo3-RGD, in which the transactivation domain CR3 of the E1A protein is ablated to enable viral replication only in YB-1 positive cancer cells. In vitro Southern Blot analysis and cytopathic effect assays demonstrate high anti-glioma potency, which was significantly increased in combination with temozolomide (TMZ), daunorubicin and cisplatin. Since vascular endothelial growth factor (VEGF) is thought to promote the hypervascular phenotype of primary, malignant brain tumors, we also tested Ad-Delo3-RGD in regard to the inhibition of VEGF expression. Indeed, we found that Ad-Delo3-RGD induced VEGF down regulation, which was even amplified under hypoxic conditions. Tumor-bearing nudemice treated with the YB-1 dependent oncolytic adenovirus showed significantly smaller tumors than untreated controls. Furthermore, combination therapy with TMZ led to a regression in all treated animals with complete tumor regression in 33 % of analyzed mice, which was verified by bioluminescence imaging and histological studies. In addition, histopathological evaluation revealed enhanced apoptosis and a reduction in tumor vessel formation, indicating that Ad-Delo3-RGD has an anti-angiogenic effect in addition to its oncolytic capacity in vivo. Hence, our results demonstrate that the combination therapy of YB-1 dependent virotherapy and TMZ is effective in a xenograft glioma mouse model and might be useful in a YB-1 based clinical setting.

本文言語English
ページ(範囲)1265-1276
ページ数12
ジャーナルInternational Journal of Cancer
129
5
DOI
出版ステータスPublished - 2011 9月 1
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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