title: ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model.
abstract: OBJECTIVE
  ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities.
  
  
  METHODS
  The triple negative human breast MDA-MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed.
  
  
  RESULTS
  Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model.
  
  
  CONCLUSIONS
  Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada; Department of Radiation Oncology, McGill University, Montreal, Canada; Segal Cancer Center, Jewish General Hospital, Montreal, Canada.
authors.forename: Mitra
authors.initials: M
authors.lastname: Heravi
authors.affiliation: Department of Radiation Oncology, McGill University, Montreal, Canada; Segal Cancer Center, Jewish General Hospital, Montreal, Canada.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kumala
authors.affiliation: Cancer Drug Research Laboratory, McGill University Health Center, Montreal, Canada.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.affiliation: Cancer Drug Research Laboratory, McGill University Health Center, Montreal, Canada.
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: Danuta
authors.initials: D
authors.lastname: Radzioch
authors.affiliation: Department of Radiation Oncology, McGill University, Montreal, Canada; Segal Cancer Center, Jewish General Hospital, Montreal, Canada. Electronic address: tmuanza@yahoo.com.
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Muanza
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D011799:Quinazolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000528:radiation effects*; D013997:Time Factors; D014226:Triazenes / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D014410:Tumor Stem Cell Assay
chemical_list: D011799:Quinazolines; D014226:Triazenes; C503825:ZRBA1 compound; D066246:ErbB Receptors