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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.
Clin Cancer Res. 2004 May 15; 10(10):3528-34.CC

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-H1607) 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.

Authors+Show Affiliations

Division of Hematology/Oncology, Department of Medicine, Simmons Cancer Center , University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15161712

Citation

Wolff, Nicholas C., et al. "Imatinib Mesylate Efficiently Achieves Therapeutic Intratumor Concentrations in Vivo but Has Limited Activity in a Xenograft Model of Small Cell Lung Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 10, no. 10, 2004, pp. 3528-34.
Wolff NC, Randle DE, Egorin MJ, et al. Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. Clin Cancer Res. 2004;10(10):3528-34.
Wolff, N. C., Randle, D. E., Egorin, M. J., Minna, J. D., & Ilaria, R. L. (2004). Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 10(10), 3528-34.
Wolff NC, et al. Imatinib Mesylate Efficiently Achieves Therapeutic Intratumor Concentrations in Vivo but Has Limited Activity in a Xenograft Model of Small Cell Lung Cancer. Clin Cancer Res. 2004 May 15;10(10):3528-34. PubMed PMID: 15161712.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. AU - Wolff,Nicholas C, AU - Randle,Dwight E, AU - Egorin,Merrill J, AU - Minna,John D, AU - Ilaria,Robert L,Jr PY - 2004/5/27/pubmed PY - 2004/12/16/medline PY - 2004/5/27/entrez SP - 3528 EP - 34 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 10 IS - 10 N2 - 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-H1607) 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15161712/Imatinib_mesylate_efficiently_achieves_therapeutic_intratumor_concentrations_in_vivo_but_has_limited_activity_in_a_xenograft_model_of_small_cell_lung_cancer_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15161712 DB - PRIME DP - Unbound Medicine ER -