title: Simultaneous PLK1 inhibition improves local tumour control after fractionated irradiation.
abstract: OBJECTIVE
  Polo-like kinase 1 (PLK1) plays an important role in mitotic progression, is frequently overexpressed and associated with a poor prognosis of cancer patients, thus providing a promising target in anticancer treatment. Aim of the current project was to evaluate the effect of the novel PLK1 inhibitor BI 6727 in combination with irradiation.
  
  
  METHODS
  In vitro proliferation and radiation cell survival assays as well as in vivo local tumour control assays after single treatment and combined radiation and drug application were carried out using the squamous cell carcinoma models A431 and FaDu. In addition, cell cycle phases were monitored in vitro and in vivo.
  
  
  RESULTS
  BI 6727 showed a dose-dependent antiproliferative effect and an increase in the mitotic fraction. BI 6727 alone reduced clonogenic cell survival, while radiosensitivity in vitro (SF2) and in vivo (single-dose TCD(50) under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD(50) = 60.5 Gy [95% C.I. 57; 63] after IR alone and <30 Gy after combined treatment; FaDu: 49.5 Gy [43; 56 Gy] versus 32.9 Gy [26; 40]).
  
  
  CONCLUSIONS
  Despite the lack of direct cellular radiosensitisation, PLK1 inhibition with BI 6727 during fractionated irradiation significantly improves local tumour control when compared to irradiation alone. This result is likely explained by a considerable effect on cell cycle and an independent cytotoxic potential of BI 6727.
authors.affiliation: Department of Radiation Oncology, Technische Universität Dresden, Germany; OncoRay-National Center for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Helmholtz-Zentrum Dresden - Rossendorf. Electronic address: mechthild.krause@uniklinikum-dresden.de.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Berit
authors.initials: B
authors.lastname: Kummer
authors.forename: Andre
authors.initials: A
authors.lastname: Deparade
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eicheler
authors.forename: Dorothee
authors.initials: D
authors.lastname: Pfitzmann
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011838:Radiation-Sensitizing Agents; D000097869:Polo-Like Kinase 1; C541363:BI 6727
keywords: Cell cycle; Combined treatment; Local tumour control; PLK1 inhibition; Radiotherapy