In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model

Radiation Oncology

Claudia Battmann²  Peter E Huber³  Jürgen Debus¹  Andreas E Kulozik²  Uwe Haberkorn⁴  Ramon Lopez Perez³  Klaus-J Weber¹  Marc Bischof¹  Albrecht Stenzinger⁵  Wilko Weichert⁵  Volker Ehemann⁵  Susanne Oertel¹  Markus Thiemann¹ 

[1] Department of Radiation Oncology, University of Heidelberg, INF 600, 69120 Heidelberg, Germany;Department of Pediatric Oncology, Hematology and Immunology, University Children's Hospital of Heidelberg, 69120 Heidelberg, Germany;Department of Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany;Department of Nuclear Medicine, University of Heidelberg and DKFZ, 69120 Heidelberg, Germany;Institute of Pathology, University of Heidelberg, 69120 Heidelberg, Germany

关键词: Suberoylanilide hydroxamic acid;    Histone deacetylase inhibition;    Radiotherapy;    In vivo;    Malignant rhabdoid tumor;   

Others  :  1160864
DOI  :  10.1186/1748-717X-7-52

 received in 2011-08-04, accepted in 2012-03-29,  发布年份 2012

【 摘 要 】

Purpose

Histone deacetylase inhibitors are promising new substances in cancer therapy and have also been shown to sensitize different tumor cells to irradiation (XRT). We explored the effect as well as the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) in vivo in a malignant rhabdoid tumor (MRT) mouse model.

Methods and material

Potential radiosensitization by SAHA was assessed in MRT xenografts by analysis of tumor growth delay, necrosis (HE), apoptosis (TUNEL), proliferation (ki-67) and γH2AX expression as well as dynamic ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography (¹⁸F-FDG -PET) after treatment with either SAHA alone, single-dose (10 Gy) or fractionated XRT (3 × 3Gy) solely as well as in combination with SAHA compared to controls.

Results

SAHA only had no significant effect on tumor growth. Combination of SAHA for 8 days with single-dose XRT resulted in a higher number of complete remissions, but failed to prove a significant growth delay compared to XRT only. In contrast fractionated XRT plus SAHA for 3 weeks did induce significant tumor growth delay in MRT-xenografts.

The histological examination showed a significant effect of XRT in tumor necrosis, expression of Ki-67, γH2AX and apoptosis. SAHA only had no significant effect in the histological examination. Comparison of xenografts treated with XRT and XRT plus SAHA revealed a significantly increased γH2AX expression and apoptosis induction in the mice tumors after combination treatment with single-dose as well as fractionated XRT. The combination of SAHA with XRT showed a tendency to increased necrosis and decrease of proliferation compared to XRT only, which, however, was not significant. The ¹⁸F-FDG-PET results showed no significant differences in the standard uptake value or glucose transport kinetics after either treatment.

Conclusion

SAHA did not have a significant effect alone, but proved to enhance the effect of XRT in our MRT in vivo model.

【 授权许可】

   
2012 Thiemann et al; licensee BioMed Central Ltd.

【 图 表 】

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