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


METHODS
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.
Wolff
Nicholas C
NC
Division of Hematology/Oncology, Department of Medicine, Simmons Cancer Center , University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Randle
Dwight E
DE
Egorin
Merrill J
MJ
Minna
John D
JD
Ilaria
Robert L
RL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D001932:Brain Neoplasms / Q000556:secondary; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D047468:Immunoprecipitation; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D014443:Tyrosine; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit