| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Nuclear Medicine and Biology | ||||
| Publisher: | ELSEVIER SCIENCE INC | ||||
| Place of Publication: | NEW YORK | ||||
| Volume: | 41 | ||||
| Number of Issue or Book Chapter: | 1 | ||||
| Page Range: | pp. 68-76 | ||||
| Date: | 2014 | ||||
| Institutions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) | ||||
| Identification Number: |
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| Keywords: | P53 TUMOR-SUPPRESSOR; NECK-CANCER; ALPHA-RADIOIMMUNOTHERAPY; PLUS CETUXIMAB; DNA-DAMAGE; HUMAN HEAD; THERAPY; IMMUNOTHERAPY; CHEMOTHERAPY; Head and neck squamous cell carcinoma; alpha-emitter Bi-213; Radioimmunotherapy; UD-SCC5 cells; Cytotoxicity; Cell-cycle arrest; Apoptosis | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 61958 |
Web of ScienceAbstract
Introduction: Treatment of patients with squamous cell carcinoma of head and neck is hampered by resistance of tumor cells to irradiation. Additional therapies enhancing the effect of X-ray irradiation may be beneficial. Antibodies targeting EGFR have been shown to improve the efficacy of radiation therapy. Therefore, we analyzed cytotoxicity of Bi-213-anti-EGFR immunoconjugates in combination ...
Abstract
Introduction: Treatment of patients with squamous cell carcinoma of head and neck is hampered by resistance of tumor cells to irradiation. Additional therapies enhancing the effect of X-ray irradiation may be beneficial. Antibodies targeting EGFR have been shown to improve the efficacy of radiation therapy. Therefore, we analyzed cytotoxicity of Bi-213-anti-EGFR immunoconjugates in combination with X-ray irradiation. Methods: The monoclonal anti-EGFR antibody matuzumab was coupled to CHX-A"-DTPA forming stable complexes with Bi-213. Cytotoxicity of X-ray radiation, of treatment with Bi-213-anti-EGFR monoclonal antibodies (MAb) or of a combined treatment regimen was assayed using cell proliferation and colony formation assays in UD-SCC5 cells. Key proteins of cell-cycle arrest and cell death were examined by Western blot analysis. Cell cycle analysis was performed by flow cytometry. DNA double-strand breaks were detected via gamma H2AX and quantified using Definiens (TM) software. Results: Irradiation with X-rays or treatment with Bi-213-anti-EGFR-MAb resulted in median lethal dose (LD50) values of 12 Gy or 130 kBq/mL, respectively. Treatment with 37 kBq/mL of Bi-213-anti-EGFR-MAb or 2 Gy of X-rays had only little effect on colony formation of UD-SCC5 cells. In contrast, a combined treatment regimen (37 kBq/mL plus 2 Gy) significantly decreased colony formation and enhanced the formation of DNA double-strand breaks. As revealed by flow cytometry, radiation treatments caused accumulation of cells in the GO/G1 phase. Both treatment with Bi-213-anti-EGFR immunoconjugates and application of the combined treatment regimen triggered activation of genes of signaling pathways involved in cell-cycle arrest and induction of apoptosis like p21/Waf, GADD45, Puma and Box, which were only marginally modulated by X-ray irradiation of cells. Conclusions: Bi-213-anti-EGFR-MAb enhances cytotoxicity of X-ray irradiation in UD-SCC5 cells most probably due to effective induction of DNA double-strand breaks. Induction of genes involved in cell-cycle arrest and cell death is almost exclusively due to Bi-213-anti-EGFR-MAb and seems to be independent of p53 function. (C) 2014 Elsevier Inc. All rights reserved.
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