Nirmitha I Herath1,2, Flavien Devun3,4, Aurélie Herbette3,4, Marie-Christine Lienafa3,4, Philippe Chouteau5, Jian-Sheng Sun3, Marie Dutreix4,6,7, Alban Denys8. 1. DNA Therapeutics, Genopole, 4 rue Pierre, Fontaine, 91058, Evry cedex, France. Nirmitha.Herath@curie.fr. 2. Institut Curie, Centre de Recherche, Bat110, Centre Universitaire, 91405, Orsay, France. Nirmitha.Herath@curie.fr. 3. DNA Therapeutics, Genopole, 4 rue Pierre, Fontaine, 91058, Evry cedex, France. 4. Institut Curie, Centre de Recherche, Bat110, Centre Universitaire, 91405, Orsay, France. 5. Team Pathophysiology and Therapy of Chronic Viral Hepatitis, Inserm U955, Université Paris-Est, Créteil, France. 6. CNRS UMR3347, Bat110, Centre Universitaire, 91405, Orsay, France. 7. INSERM U1021, Bat110, Centre Universitaire, 91405, Orsay, France. 8. Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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.
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.
Authors: Pierre Bize; Rafael Duran; Katrin Fuchs; Olivier Dormond; Julien Namur; Laurent A Decosterd; Olivier Jordan; Eric Doelker; Alban Denys Journal: Radiology Date: 2016-02-26 Impact factor: 11.105
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Authors: Poyil Pratheeshkumar; Amit Budhraja; Young-Ok Son; Xin Wang; Zhuo Zhang; Songze Ding; Lei Wang; Andrew Hitron; Jeong-Chae Lee; Mei Xu; Gang Chen; Jia Luo; Xianglin Shi Journal: PLoS One Date: 2012-10-18 Impact factor: 3.240