| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Cytometry Part A | ||||
| Publisher: | WILEY-BLACKWELL | ||||
| Place of Publication: | HOBOKEN | ||||
| Volume: | 79A | ||||
| Number of Issue or Book Chapter: | 9 | ||||
| Page Range: | pp. 684-693 | ||||
| Date: | 2011 | ||||
| Institutions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) | ||||
| Identification Number: |
| ||||
| Keywords: | MONOCLONAL-ANTIBODY; KINASE INHIBITOR; LAPATINIB GW572016; TUMOR-CELLS; IN-VITRO; TRASTUZUMAB; HERCEPTIN; HER2/NEU; HETERODIMERIZATION; PERTUZUMAB; Lapatinib; Trastuzumab; Pertuzumab; growth factors; anti-Her2 targeting; BrdU/Hoechst quenching; breast cancer cell lines | ||||
| 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: | 64622 |
Web of ScienceAbstract
Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor- and, in turn, growth-stimulating effects, which potentially hamper ...
Abstract
Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor- and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRG-caused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. (C) 2011 International Society for Advancement of Cytometry
Metadata last modified: 19 Dec 2024 11:08
Altmetric