Original article Strahlenther Onkol 2014 DOI 10.1007/s00066-014-0686-1 Received: 3 March 2014 Accepted: 28 April 2014

Nils H. Nicolay1,2 · Eva Sommer2 · Ramon Lopez Perez2 · Ute Wirkner2 · Tilman Bostel1 · Anthony D. Ho3 · Michael Lahn4 · Jürgen  Debus1,2 · Rainer  Saffrich3 · Peter E. Huber1,2

© Springer-Verlag Berlin Heidelberg 2014

2Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz),

1Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany

Heidelberg, Germany 3Department of Hematology, Oncology and Rheumatology,

Heidelberg University Hospital, Heidelberg, Germany 4Oncology Early Clinical Investigation, Lilly Research Laboratories, Indianapolis, IN, USA

Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation Mesenchymal stem cells (MSCs) have become a research focus due to their potential to regenerate damaged tissue. MSCs are believed to facilitate tissue repair by virtue of their ability to differentiate into functional cells and via the secretion of growth factors and cytokines [1]. Several preclinical studies have shown beneficial effects of MSC engraftment for organs and tissues such as heart, lung, skin, cartilage and nerve tissues [2–6]. Radiotherapy is an important treatment option for cancer patients. Radiotherapy exerts many of its effects by targeting and damaging the DNA of tumor cells; depending on the type and amount of damage inflicted, tumor cells fail to recognize or repair the lesions, resulting in cell cycle arrest, apoptosis or mutagenesis. Individual tissues reveal considerably different sensitivities to ionizing radiation (IR; [7, 8]). Apart from cellular factors, such as cell cycle distribution and the capacity for DNA repair, various cytokines and other components of the cellular microenvironment have been credited with determining a tissue’s radiation sensitivity [9–12]. In recent years, a new group of “biological” cancer therapeutic agents that work by blocking cellular growth factor receptors have entered clinical routine. Based on preclinical findings, several clinical

studies have revealed beneficial effects for some of these growth factor receptor-inhibiting drugs when combined with other cancer treatments such as radiotherapy [13, 14]. Intriguingly, some drugs—including inhibitors of platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) signaling—have not only shown antitumor effects alone and in combination with radiotherapy [15–18], but have been shown to attenuate idiopathic [19] and radiation-induced lung fibrosis [18, 20]. MSCs have been suggested to have an important role in the development of fibrosis [21]. Therefore, as the aforementioned drugs also exert effects on the cellular growth and differentiation of healthy tissues, a more detailed, cell type-specific analysis is warranted. In this study, we examined the response of human MSCs to receptor kinase inhibitors (RKIs) alone and in combination treatments incorporating kinase blockade and irradiation.

terized as previously described [22, 23]. After isolation, MSCs were proliferated in Mesenchymal Stem Cell Basal Medium (Lonza, Cologne, Germany) supplemented with MSCGM SingleQuots (Lonza). All MSCs were harvested after obtaining written consent according to the ethical guidelines set down by the University of Heidelberg and the study was approved by the respective ethics board. Untransformed normal primary human dermal fibroblasts (NHDFs) and HS68 human fibroblast cells were obtained from Promocell (Heidelberg, Germany) and the American Type Culture Collection (ATCC, Manassas, VA, USA), respectively. NHDFs were grown in Endothelial Cell Basal Medium (Promocell) with the addition of 500 µg/L gentamycin and 0.01 µg/L amphothericin B. HS68 cells were maintained in Dulbecco’s Modified Eagle Medium (Biochrom, Berlin, Germany) supplemented with 10 % fetal calf serum and 3.5 g/L glucose.

Materials and methods

Drug preparation and treatment

Cell lines and cultures

The selective class III/V tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib analogue) were obtained from SUGEN (San Francisco, CA, USA) and Pfizer (Karlsruhe, Germany), respectively; the TGF β receptor type I

Primary human MSCs MSC283, MSC284 and MSC285 were derived from bone marrow samples of three healthy donors. These were purified and charac-

Strahlentherapie und Onkologie X · 2014 

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Original article SU14816 1.2

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Fig. 1 8 Survival of mesenchymal stem cells (MSCs) is strongly reduced by receptor kinase inhibitors (RKIs). Clonogenic survival of MSC283, MSC284, MSC285, adult normal primary human dermal fibroblasts (NHDF) and HS68 fibroblasts after a 2-hour treatment with inhibitors SU14816 (a), SU11657 (b) or LY2109761 (c). d Alterations in MSC morphology after treatment with SU11657. (20X objective, scale bar 100 µm). Statistical analysis performed using student’s t-tests: *P 

Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation.

Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small...
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