Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms
| Autor: | Bernard Dutrillaux, Stéphane Oudard, M.F. Poupon, P. de Cremoux, Marie-Emmanuelle Legrier, G de Pinieux, Charlotte Guyader, J.G. Judde, Karine Boyé |
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| Rok vydání: | 2007 |
| Předmět: |
Male
prostate adenocarcinoma Cancer Research medicine.medical_specialty medicine.drug_class Blotting Western Transplantation Heterologous Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Docetaxel Antibodies Monoclonal Humanized Monoclonal antibody Receptor tyrosine kinase Prostate cancer drug evaluation Trastuzumab Internal medicine Humans Medicine skin and connective tissue diseases protein expression neoplasms DNA Primers potentiation Base Sequence biology Reverse Transcriptase Polymerase Chain Reaction business.industry Antibodies Monoclonal Prostatic Neoplasms Cancer Biological activity medicine.disease Hsp90 Endocrinology Oncology biology.protein Cancer research Taxoids Translational Therapeutics business medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6603553 |
| Popis: | Antitumour activity of docetaxel (Taxotere®) in hormone-dependent (HD) and hormone-independent (HID) prostate cancer PAC120 xenograft model was previously reported, and its level was associated with HER2 protein expression. In the present study, we evaluate the antitumour effects of docetaxel combined with trastuzumab (Herceptin®), an anti-HER2 antibody. Although trastuzumab alone had no effect on tumour growth, it potentiated the antitumour activity of docetaxel in HD tumours and more strongly in HID variants. Using the HID28 variant, we show that docetaxel treatment of tumour-bearing mice induces an increased HER2 mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel treatment, while HER2 protein and p-AKT decreased. This was followed by an increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a strong HER2 release in the serum of treated mice; expression of phospho-ERK, p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment. We show that in addition to its known effects on tubulin and mitotic spindles, docetaxel induces complex signalisation pathway mechanisms in surviving cells, including HER2, which can be pharmacologically targeted. This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer. |
| Databáze: | OpenAIRE |
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