Artikel
Lapatinib and cisplatin synergise in suppression of head and neck squamous cell carcinoma ex vivo
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Veröffentlicht: | 22. April 2010 |
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Gliederung
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Introduction: The tyrosine-kinase inhibitor (TKI) lapatinib is introduced into multimodal therapy of advanced head and neck squamous cell carcinoma (HNSCC).
Purpose: To analyze the dose-response curve of lapatinib and whether this TKI combined with cisplatin exerts synergistic suppressive effects on HNSCC in a short-time ex-vivo colony-forming assay – flavin-protecting conditions (FLAVINO).
Methods: Biopsies of 72 HNSCC were taken, minced, collagenase-digested and added into microtiterplates containing serial lapatinib dilutions or medium plus solvent control (DMSO). The same lapatinib concentrations were tested also in combination with cisplatin (1.67, 3.33, or 6.67 µM, corresponding to ¼, ½, or exactly its tolerable plasma level). After 3-d incubation, wells were washed and cells ethanol-fixed. Fluorescent colonies were counted after pan-cytokeratin staining of epithelial cells using a fluorescent-labeled antibody.
Results: 64.7% of HNSCC growing in-vitro showed sufficient colony formation that allows for reliable cut-off detection. Cut-off (complete chemotherapeutical-suppressed colony formation) was achieved either by 6.25 µM lapatinib or 3.33 µM cisplatin alone only in three (9.1%) and in one HNSCC, respectively. The doubled number (eight HNSCC=24.2%) reached cut-off if treated with mixtures of 6.25 µM lapatinib and 3.33 µM cisplatin. The synergism of lapatinib and cisplatin is also reflected by the dose-response curves’ slope and the decreasing IC50 concentrations (50%-inhibition of colony-formation) of lapatinib which were 3.17, 3.21, 0.83, and 0.19 µM in the presence of 0.00, 1.67, 3.33, and 6.67 µM cisplatin.
Conclusions: The ex-vivo results in the FLAVINO assay indicate synergism of lapatinib with cisplatin toward suppressive activity on HNSCC.
This work was supported by GlaxoSmithKline