Simultaneous PLK1 inhibition improves local tumour control after fractionated irradiation

Abstract Purpose 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 nove...

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Bibliographic Details
Published in:Radiotherapy and oncology 2013-09, Vol.108 (3), p.422-428
Main Authors: Krause, Mechthild, Kummer, Berit, Deparade, Andre, Eicheler, Wolfgang, Pfitzmann, Dorothee, Yaromina, Ala, Kunz-Schughart, Leoni A, Baumann, Michael
Format: Article
Language:English
Subjects:
Animals
Cell cycle
Cell Cycle - drug effects
Cell Cycle Proteins - antagonists & inhibitors
Cell Line, Tumor
Combined treatment
Female
Hematology, Oncology and Palliative Medicine
Humans
Local tumour control
Male
Mice
Neoplasms - pathology
Neoplasms - radiotherapy
PLK1 inhibition
Polo-Like Kinase 1
Protein Serine-Threonine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - antagonists & inhibitors
Pteridines - pharmacology
Radiation-Sensitizing Agents - pharmacology
Radiotherapy
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Summary:Abstract Purpose 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. Material and 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 TCD50 under clamped hypoxia) was not affected. In contrast, local tumour control was significantly improved after application of BI 6727 simultaneously to fractionated irradiation (A431: TCD50 = 60.5 Gy [95% C.I. 57; 63] after IR alone and
ISSN:0167-8140
1879-0887
DOI:10.1016/j.radonc.2013.06.038