The effect of imatinib mesylate (Glivec) on human tumor-derived cells

Louise A. Knight, Federica Di Nicolantonio, Pauline A. Whitehouse, Stuart J. Mercer, Sanjay Sharma, Sharon Glaysher, John L. Hungerford, Jeremy Hurren, Alan Lamont, Ian A. Cree

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Abstract

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-α and -β), 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 μmol/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 μmol/l (4.0-294.3 μmol/l), 12.0 μmol/l (2.0-285.4 μmol/l) and 7.71 μmol/l (6.51-11.02 μmol/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-α or platelet-derived growth factor receptor-β 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.

Original languageEnglish
Pages (from-to)649-655
Number of pages7
JournalAnti-Cancer Drugs
Volume17
Issue number6
DOIs
Publication statusPublished - Jul 2006

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Keywords

  • ATP-tumor chemosensitivity assay
  • Chemosensitivity
  • Glivec
  • Imatinib

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Knight, L. A., Nicolantonio, F. D., Whitehouse, P. A., Mercer, S. J., Sharma, S., Glaysher, S., Hungerford, J. L., Hurren, J., Lamont, A., & Cree, I. A. (2006). The effect of imatinib mesylate (Glivec) on human tumor-derived cells. Anti-Cancer Drugs, 17(6), 649-655. https://doi.org/10.1097/01.cad.0000215062.16308.41