title: The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis.
abstract: Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm(2), P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer.
authors.affiliation: Recombination, Repair and Cancer Laboratory, Institut Curie, Centre de Recherche, Orsay, France. DNA Therapeutics, Genopole, Evry, France. nirmitha.herath@curie.fr.
authors.forename: Nirmitha I
authors.initials: NI
authors.lastname: Herath
authors.affiliation: Recombination, Repair and Cancer Laboratory, Institut Curie, Centre de Recherche, Orsay, France. DNA Therapeutics, Genopole, Evry, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Devun
authors.affiliation: Recombination, Repair and Cancer Laboratory, Institut Curie, Centre de Recherche, Orsay, France. DNA Therapeutics, Genopole, Evry, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Lienafa
authors.affiliation: Recombination, Repair and Cancer Laboratory, Institut Curie, Centre de Recherche, Orsay, France. DNA Therapeutics, Genopole, Evry, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Herbette
authors.affiliation: Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Alban
authors.initials: A
authors.lastname: Denys
authors.affiliation: DNA Therapeutics, Genopole, Evry, France.
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Sun
authors.affiliation: Recombination, Repair and Cancer Laboratory, Institut Curie, Centre de Recherche, Orsay, France. CNRS UMR3347, Centre Universitaire, Orsay, France. INSERM U120, Centre Universitaire, Orsay, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004247:DNA / Q000008:administration & dosage / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary*; D051379:Mice; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000611563:DT01 compound; D004247:DNA; D002784:Cholesterol; D005472:Fluorouracil