title: Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer.
abstract: BACKGROUND
  Dbait molecules are a new class of DNA repair inhibitors triggering false DNA damage signaling in cancer cells. Dbait has already been shown to be effective in combination with radiotherapy. The aim of this study was to assess the adjuvant impact of Dbait on chemotherapy in vitro and in mouse models of colorectal cancer.
  
  
  METHODS
  We assessed DNA repair efficiency over time, in vitro, in human colon adenocarcinoma HT-29 (wild-type KRAS) and HCT-116 (mutated KRAS) cell lines treated with Dbait in combination with 5-fluorouracil and/or camptothecin. Genetically engineered mice spontaneously developing colorectal tumors in the intestines were selected for the evaluation of treatment efficacy.
  
  
  RESULTS
  Dbait delayed the repair of DNA damage induced by chemotherapy in vitro. In APC (+/1638N) mutant mice, the combination of Dbait and chemotherapy decreased tumor size more effectively than chemotherapy alone (median size: 3.6 vs. 10.85 mm(2), P < 0.05). In APC (+/1638N)/KRAS ( V12G ) mutant mice, animals treated with a combination of Dbait and chemotherapy survived significantly longer than animals treated by chemotherapy alone (median survival: 210 vs. 194 days, P < 0.05). A quarter of all the animals treated by chemotherapy alone died as rapidly as untreated animals, whereas the first death was delayed by 29 days by the addition of Dbait. No increase in toxicity due to Dbait was observed in either mouse model.
  
  
  CONCLUSIONS
  The use of Dbait to inhibit DNA repair may be an effective additional treatment for increasing the efficacy of chemotherapy in colon or rectal cancer, independently of KRAS status.
authors: Institut Curie, Equipe Dutreix, Bat 110, Research Centre, Centre Universitaire, 91405 Paris-Orsay, France. flavien.devun@curie.fr
authors: Flavien
authors: F
authors: Devun
authors: Guilhem
authors: G
authors: Bousquet
authors: Julian
authors: J
authors: Biau
authors: Aurélie
authors: A
authors: Herbette
authors: Christophe
authors: C
authors: Roulin
authors: Frédérique
authors: F
authors: Berger
authors: Jian-Sheng
authors: JS
authors: Sun
authors: Sylvie
authors: S
authors: Robine
authors: Marie
authors: M
authors: Dutreix
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D005472:Fluorouracil / Q000008:administration & dosage; D005818:Genetic Engineering; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013997:Time Factors; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D005472:Fluorouracil; D002166:Camptothecin