The Selective Tyrosine Kinase Inhibitor STI571 Inhibits Small Cell Lung Cancer Growth

At least 70% of small cell lung cancers express the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Numerous lines of evidence have demonstrated that this coexpression constitutes a functional autocrine loop, suggesting that inhibitors of Kit tyrosine kinase activity could have...

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Bibliographic Details
Published in:Clinical cancer research 2000-08, Vol.6 (8), p.3319-3326
Main Authors: KRYSTAL, G. W, HONSAWEK, S, LITZ, J, BUCHDUNGER, E
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Benzamides
Biological and medical sciences
Carboplatin - pharmacology
Carcinoma, Small Cell - drug therapy
Carcinoma, Small Cell - pathology
Cell Division - drug effects
Dose-Response Relationship, Drug
Drug Synergism
Enzyme Activation - drug effects
Enzyme Inhibitors - pharmacology
General aspects
Growth Inhibitors - pharmacology
Humans
Imatinib Mesylate
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Medical sciences
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - metabolism
Pharmacology. Drug treatments
Piperazines - pharmacology
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-kit - metabolism
Pyrimidines - pharmacology
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - metabolism
Stem Cell Factor - antagonists & inhibitors
Tumor Cells, Cultured - drug effects
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Summary:At least 70% of small cell lung cancers express the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Numerous lines of evidence have demonstrated that this coexpression constitutes a functional autocrine loop, suggesting that inhibitors of Kit tyrosine kinase activity could have therapeutic efficacy in this disease. STI571, formerly known as CGP 57148B, is a p.o. bioavailable 2-phenylaminopyrimide derivative that was designed as an Abl tyrosine kinase inhibitor, but also has efficacy against the platelet-derived growth factor receptor and Kit in vitro . Pretreatment of the H526 small cell lung cancer (SCLC) cell line with STI571 inhibited SCF-mediated Kit activation with an IC 50 of 0.1 μ m as measured by inhibition of receptor tyrosine phosphorylation and 0.2 μ m as measured by immune complex kinase assay. This paralleled the inhibition of SCF-mediated growth by STI571, which had an IC 50 of∼ 0.3 μ m . Growth inhibition in SCF-containing medium was accompanied by induction of apoptosis. STI571 efficiently blocked SCF-mediated activation of mitogen-activated protein kinase and Akt, but did not affect insulin-like growth factor-1 or serum-mediated mitogen-activated protein kinase or Akt activation. Growth of five of six SCLC cell lines in medium containing 10% FCS was inhibited by STI571 with an IC 50 of ∼5 μ m . Growth inhibition in serum-containing medium appeared to be cytostatic in nature because no increase in apoptosis was observed. Despite this growth inhibition, STI571 failed to enhance the cytotoxicity of either carboplatinum or etoposide when coadministered. However, taken together with the minimal toxicity that this compound has shown in preclinical studies, these data suggest that STI571 could have a role in the treatment of SCLC, possibly to block or slow recurrence after chemotherapy-induced remissions.
ISSN:1078-0432
1557-3265