Differences in radiosensitivity between three HER2 overexpressing cell lines
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HER2 is a potential target for radionuclide therapy, especially when HER2 overexpressing breast cancer cells are resistant to Herceptin® treatment. Therefore, it is of interest to analyse whether HER2 overexpressing tumour cells have different inherent radiosensitivity.
The radiosensitivity of three often used HER2 overexpressing cell lines, SKOV-3, SKBR-3 and BT-474, was analysed. The cells were exposed to conventional photon irradiation, low linear energy transfer (LET), to characterise their inherent radiosensitivity. The analysis was made with clonogenic survival and growth extrapolation assays. The cells were also exposed to alpha particles, high LET, from 211At decays using the HER2-binding affibody molecule 211At-(ZHER2:4)2 as targeting agent. Assays for studies of internalisation of the affibody molecule were applied.
SKOV-3 cells were most radioresistant, SKBR-3 cells were intermediate and BT-474 cells were most sensitive as measured with the clonogenic and growth extrapolation assays after photon irradiation. The HER2 dependent cellular uptake of 211At was qualitatively similar for all three cell lines. However, the sensitivity to the alpha particles from 211At differed; SKOV-3 was most resistant, SKBR-3 intermediate and BT-474 most sensitive. These differences were unexpected because it is assumed that all types of cells should have similar sensitivity to high-LET radiation. The sensitivity to alpha particle exposure correlated with internalisation of the affibody molecule and with size of the cell nucleus.
There can be differences in radiosensitivity, which, if they also exist between patient breast cancer cells, are important to consider for both conventional radiotherapy and for HER2-targeted radionuclide therapy.
KeywordsErbB2 HER2 High LET Nuclear medicine Radiation effects Tumour cells
The authors thank Veronika Asplund Eriksson for help with the clonogenic survival assay, low-LET irradiation procedures and cell- and nuclear size determinations; Jan Grawé for help with confocal microscopy and flow cytometry; and Fredrik Nilsson and Anders Wennborg at Affibody AB for providing the affibody molecules used in this study and for fruitful discussions. Thanks also to Holger Jensson at Rigshospitalet in Copenhagen, Denmark, for production and delivery of 211At. The work was financially supported by the Swedish Cancer Society, grant no 0980-B06-19XBC (060078). The experimental procedures comply with Swedish laws on radiological and general laboratory work.
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