The effect of imatinib mesylate (Glivec) on human tumor-derived cells
| Autor: | Sharon Glaysher, Sanjay Sharma, Louise A. Knight, Alan Lamont, Jeremy Hurren, Stuart Mercer, Pauline A. Whitehouse, Ian A. Cree, Federica Di Nicolantonio, John L. Hungerford |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Uveal Neoplasms Cancer Research Skin Neoplasms medicine.medical_treatment Antineoplastic Agents Piperazines Immunoenzyme Techniques chemistry.chemical_compound Growth factor receptor Cell Line Tumor medicine Humans Pharmacology (medical) Melanoma Aged Pharmacology Cisplatin Ovarian Neoplasms business.industry Growth factor Imatinib Middle Aged Protein-Tyrosine Kinases Imatinib mesylate Pyrimidines Oncology chemistry Benzamides Cancer research Imatinib Mesylate Female Growth inhibition business Chemosensitivity assay Tyrosine kinase medicine.drug Signal Transduction |
| Zdroj: | Anti-cancer drugs. 17(6) |
| ISSN: | 0959-4973 |
| Popis: | Imatinib mesylate is a specific inhibitor of the Bcr-Abl protein tyrosine kinase that competes with ATP for its specific binding site in the kinase domain. It has activity against platelet-derived growth factor receptor alpha and beta (PDGFR-alpha and -beta), and c-kit, the receptor for stem cell factor. We have used a standardized ATP-tumor chemosensitivity assay and immunohistochemistry to determine the cytotoxicity of imatinib mesylate in tumor-derived cells from cutaneous and uveal melanoma, and ovarian carcinoma. Imatinib mesylate was tested at concentrations ranging from 2.0 to 0.0625 micromol/l alone and in combination with a cytotoxic drug (cisplatin, doxorubicin, paclitaxel or treosulfan). Imatinib mesylate showed low inhibition (IndexSUM>300) across the range of concentrations tested in this study, with few tumors exhibiting increasing inhibition with increased drug concentration. The median IC90 values for cutaneous and uveal melanoma and ovarian carcinoma were 13.2 micromol/l (4.0-294.3 micromol/l), 12.0 micromol/l (2.0-285.4 micromol/l) and 7.71 micromol/l (6.51-11.02 micromol/l), respectively. Imatinib mesylate potentiated the effect of different cytotoxics in 9% (5/54) of cases and had a negative effect in 13% (7/54) of cases, with no effect in the remainder. No correlation of effect was noted with c-kit, platelet-derived growth factor receptor-alpha or platelet-derived growth factor receptor-beta expression, assessed by immunohistochemistry. The signaling pathways mediated by activation of c-kit or platelet-derived growth factor receptor may act as antiapoptotic survival signals in some cancers and inhibition of these pathways may potentiate the activity of some cytotoxic drugs by inhibiting the survival signal. Growth inhibition, however, may reduce the efficacy of cytotoxic drugs, which tend to target proliferating cells preferentially, and clinical effects are therefore difficult to predict. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|