The DNA repair inhibitor DT01 as a novel therapeutic strategy for chemo-sensitization of colorectal liver metastasis
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une stratégie basée sur l'inhibition d'enzymes impliquées dans la réparation de l'ADN renforce l'efficacité d'une chimiothérapie visant à supprimer les métastases hépatiques d'un cancer colorectal
Metastatic liver disease from colorectal cancer (CRC) is a significant clinical problem. This is mainly attributed to non-resectable 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 CRC 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 activate damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 CRC 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 CRC liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant anti-tumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs 872 mm2, p=0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histological 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.
http://mct.aacrjournals.org/content/early/2015/12/04/1535-7163.MCT-15-0408.abstract 2015