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Potentiation of doxorubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models

  • Gastrointestinal
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objective

This study aimed to explore the antitumour effect of the DNA repair inhibitor, DT01 (the cholesterol conjugated form of Dbait), as an adjunct treatment to enhance the therapeutic efficacy of transarterial chemoembolization (TACE) in pre-clinical models of hepatocellular carcinoma (HCC).

Methods

A rabbit model bearing liver tumours was either left untreated or treated with TACE or with a combination of TACE+DT01. Tumour growth was monitored by ultrasound. These results were further confirmed in mice grafted with an intrahepatic human HCC model treated with doxorubicin (DOX) alone or DOX+DT01.

Results

The combination of DT01 with TACE in a rabbit liver model led to a significant decrease in tumour volume (p=0.03). Colour Doppler and immunohistochemical staining revealed a strong decrease in vascularization in the DT01+TACE-treated group preventing the tumour growth restart observed after TACE alone. Similarly, the DT01 combination with DOX led to significant anti-tumour efficacy compared to DOX alone (p=0.02) in the human HCC model. In addition, a significant decrease in vascularization in the group receiving combination DT01 and DOX treatment was observed.

Conclusions

DT01 is well tolerated and may potentiate HCC treatment by enhancing the DNA-damaging and anti-vascularization effect of TACE with doxorubicin.

Key points

• DT01 combined with TACE leads to significant anti-tumour efficacy without additional toxicity.

• A potential anti-angiogenic role of DT01 was identified in preclinical models.

• DT01 may potentiate HCC treatment by enhancing the efficacy of TACE.

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Abbreviations

CCl4 :

Carbon tetrachloride

CD31:

Cluster of differentiation 31

DNA-PK:

DNA-dependent protein kinase

DOX:

Doxorubicin

DSB:

Double strand break

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

IP:

Intraperitoneal

MNi:

Micronuclei

MVD:

Microvessel density

TACE:

Transarterial chemoembolization

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor

VX2:

Carcinoma cells derived from virus-induced papilloma of rabbits

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Acknowledgements

The authors would like to thank Sophie Dodier for histological services (Histology platform, Institut Curie), Prof. Michel Huerre for analyses of histological sections and Mr. André Nicolas for scanning of histological sections (Pathology service, l’hôpital Curie). This study was also supported by the technical staff of the Institut Curie animal facility. The authors would further like to thank Florentina Pascale (Archimmed, Jouy en Josas) for facilitating the TACE study.

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Author notes

    Authors and Affiliations

    1. DNA Therapeutics, Genopole, 4 rue Pierre, Fontaine, 91058, Evry cedex, France

      Nirmitha I. Herath, Flavien Devun, Aurélie Herbette, Marie-Christine Lienafa & Jian-Sheng Sun

    2. Institut Curie, Centre de Recherche, Bat110, Centre Universitaire, 91405, Orsay, France

      Nirmitha I. Herath, Flavien Devun, Aurélie Herbette, Marie-Christine Lienafa & Marie Dutreix

    3. Team Pathophysiology and Therapy of Chronic Viral Hepatitis, Inserm U955, Université Paris-Est, Créteil, France

      Philippe Chouteau

    4. CNRS UMR3347, Bat110, Centre Universitaire, 91405, Orsay, France

      Marie Dutreix

    5. INSERM U1021, Bat110, Centre Universitaire, 91405, Orsay, France

      Marie Dutreix

    6. Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

      Alban Denys

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    1. Nirmitha I. Herath
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    Correspondence to Nirmitha I. Herath.

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    Guarantor

    The scientific guarantor of this publication is Dr. Marie Dutreix

    Conflict of interest

    JSS and MD declare relationships with DNA Therapeutics.

    Funding

    This study has received funding by DNA Therapeutics and the Translational Department of Institut Curie.

    Statistics and biometry

    No complex statistical methods were necessary for this paper.

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    Approval from the institutional animal care committee was obtained.

    Methodology

    • prospective

    • experimental

    • multicentre study

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    Nirmitha I. Herath and Flavien Devun are co-first authors.

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    Herath, N.I., Devun, F., Herbette, A. et al. Potentiation of doxorubicin efficacy in hepatocellular carcinoma by the DNA repair inhibitor DT01 in preclinical models. Eur Radiol 27, 4435–4444 (2017). https://doi.org/10.1007/s00330-017-4792-1

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