Seitz, Stephan and Buchholz, Stefan and Schally, Andrew Victor and Weber, Florian and Klinkhammer-Schalke, Monika and Inwald, Elisabeth C. and Perez, Roberto and Rick, Ferenc G. and Szalontay, Luca and Hohla, Florian and Segerer, Sabine and Kwok, Chui Wai and Ortmann, Olaf and Engel, Joerg Bernhard (2014) Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125. BMC CANCER, 14: 847. ISSN 1471-2407,
Full text not available from this repository. (Request a copy)Abstract
Background: Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z. Methods: 69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH-receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.). Results: In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69). HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective. As compared to AEZS 108, the Disorazol Z - LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment. Conclusion: The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HORMONE-RELEASING-HORMONE; EPIDERMAL-GROWTH-FACTOR; HIGH-AFFINITY BINDING; ANTAGONIST CETRORELIX; GYNECOLOGICAL CANCERS; CELL-LINES; DOXORUBICIN; INHIBITION; OVARIAN; CHEMOTHERAPY; Targeted therapy; Triple negative breast cancer; LHRH-receptor; AEZS 108; AEZS 125 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie Medicine > Zentren des Universitätsklinikums Regensburg > Tumorzentrum e.V. |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Aug 2019 07:46 |
| Last Modified: | 08 Aug 2019 07:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9196 |
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