Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer

Nicholas C. Wolff, Dwight E. Randle, Merrill J. Egorin, John D. Minna, Robert L. Ilaria

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Abstract

Purpose: Despite recent advances in cancer therapy, long-term survival in small cell lung cancer (SCLC) remains uncommon, underscoring the need for novel therapeutic approaches. Previous studies have identified constitutive expression of the receptor tyrosine kinase, c-Kit, and its ligand, stem cell factor, in a substantial proportion of SCLC specimens. The purpose of this study was to determine whether imatinib mesylate, an inhibitor of c-Kit, could achieve therapeutic concentrations in tumors and in brain (a frequent site of SCLC metastasis) and interfere with SCLC tumor growth in vivo. Experimental Design: Human SCLC tumor cell lines with constitutive c-kit expression and tyrosine phosphorylation (NCI-H209, NCI-H526, and NCI-HI607) were used to establish SCLC tumor xenografts in NCr nude (nu/nu)-immunodeficient mice. SCLC tumor-bearing mice were randomly assigned to imatinib or control (water) administered twice a day by oral gavage. Imatinib concentrations in plasma, brain, and tumor were quantitated and correlated with tumor response. Results: Therapeutic concentrations of imatinib were achieved in plasma and tumor xenografts but not in the brain. Imatinib blocked the constitutive activation of c-kit in SCLC tumor cell lines in vitro but had a negligible effect on SCLC xenograft growth in vivo. Conclusions: Orally administered imatinib rapidly reaches therapeutic concentrations in SCLC xenografts, suggesting the feasibility of combining imatinib with other novel or traditional chemotherapeutic agents in SCLC or other solid tumors. The c-Kit signaling pathway does not appear to play a critical role in SCLC proliferation and viability in vivo, however, suggesting that imatinib is unlikely to be effective as monotherapy for SCLC.

Original languageEnglish (US)
Pages (from-to)3528-3534
Number of pages7
JournalClinical Cancer Research
Volume10
Issue number10
DOIs
StatePublished - May 15 2004

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Small Cell Lung Carcinoma
Heterografts
Therapeutics
Neoplasms
Stem Cell Factor
Tumor Cell Line
Brain Neoplasms
Imatinib Mesylate
Receptor Protein-Tyrosine Kinases
Growth
Tyrosine
Research Design
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. / Wolff, Nicholas C.; Randle, Dwight E.; Egorin, Merrill J.; Minna, John D.; Ilaria, Robert L.

In: Clinical Cancer Research, Vol. 10, No. 10, 15.05.2004, p. 3528-3534.

Research output: Contribution to journalArticle

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