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1 July 2008 Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines
Dirk Bottke, Daniel Koychev, Antonia Busse, Karin Heufelder, Thomas Wiegel, Eckhard Thiel, Wolfgang Hinkelbein, Ulrich Keilholz
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Abstract

Bottke, D., Koychev, D., Busse, A., Heufelder, K., Wiegel, T., Thiel, E., Hinkelbein, W. and Keilholz, U. Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines. Radiat. Res. 170, 41–48 (2008).

The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.

Dirk Bottke, Daniel Koychev, Antonia Busse, Karin Heufelder, Thomas Wiegel, Eckhard Thiel, Wolfgang Hinkelbein, and Ulrich Keilholz "Fractionated Irradiation Can Induce Functionally Relevant Multidrug Resistance Gene and Protein Expression in Human Tumor Cell Lines," Radiation Research 170(1), 41-48, (1 July 2008). https://doi.org/10.1667/RR0986.1
Received: 5 February 2007; Accepted: 1 February 2008; Published: 1 July 2008
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