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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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.
Ethical approval
Approval from the institutional animal care committee was obtained.
Methodology
• prospective
• experimental
• multicentre study
Additional information
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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DOI: https://doi.org/10.1007/s00330-017-4792-1