A Preclinical Study Combining the DNA Repair Inhibitor Dbait with Radiotherapy for the Treatment of Melanoma

• DOI: 10.1016/j.neo.2014.08.008
• Publication Date: 2014-10-23T19:04:08Z
• Authors: Julian Biau; Flavien Devun; Wael Jdey; Ewa Kotula; Maria Quanz; Emmanuel Chautard; Mano Sayarath; Jian-Sheng Sun; Pierre Verrelle; Marie Dutreix
• Keywords: Radioresistance

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair.Dbait (which stands for strand bait) molecules mimic DSBs and trap repair proteins, thereby inhibiting of damage induced by radiation therapy (RT).First, the cytotoxic efficacy Dbait in combination with RT was evaluated vitro SK28 501mel human melanoma cell lines.Though extent RT-induced not increased Dbait, it persisted longer revealing a defect.Dbait enhanced independently doses.We further assayed capacity DT01 (clinical form Dbait) enhance "palliative" (10 × 3 Gy) or "radical" (20 Gy), an xenografted model.Inhibition RTinduced DSB revealed significant increase micronuclei tumors treated combined treatment.Mice had significantly better tumor growth control survival compared alone protocol [tumor delay (TGD) 5.7-fold; median survival: 119 vs 67 days] (TGD 3.2-fold; 221 109 days).Only animals that received treatment showed complete responses.No additional toxicity observed any DT01-treated groups.This preclinical study provides encouraging results new inhibitor, DT01, RT, absence toxicity.A first-in-human phase I is currently under way palliative management in-transit metastases (DRIIM trial).