In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy

Abstract

Tyrosine kinase proteins play a crucial role in the transduction of intracellular signals, leading to various cellular responses, such as proliferation, apoptosis and differentiation. 1,2 These enzymes are therefore becoming new targets in antitumor therapies designed to block tumor growth, metastasis and neoangiogenesis and to trigger tumor cell apoptosis. 3,4 The tyrosine kinase inhibitor, STI571, belonging to the 2-phenylaminopyrimidine class, formerly known as CGP57148B, selectively inhibits BCR/ABL, 5 platelet-derived growth factor receptor (PDGFR) and c-kit kinase activity. 6 Numerous publications have shown preclinical and clinical efficacy of STI571 on these 3 identified targets: (i) via inhibition of ABL kinase activity in chronic myeloid leukemia (CML) in chronic phase or acute lymphoblastic leukemia with t(9;22)(q34;q11); 7,8 (ii) via PDGFR, CML with PDGFR␣ rearrangement, 9 idiopathic hypereosinophilic syndrome, 10 dermatofibrosarcoma protuberans, [11][12][13] SCLC appears to be an appropriate target for STI571 therapy, as 36% to more than 70% of SCLC tumors and cell lines express c-kit transcript or protein. 29 -38 The growth and viability of a number of SCLC cell lines were inhibited in a dose-dependent fashion by STI571 27,28 and by adenovirus vectors expressing antisense c-kit transcript; 26 in vitro data have shown that STI571 inhibits cell growth and viability via a mechanism involving inactivation of the tyrosine kinase c-kit. 28 This effect appears to be cytostatic because no increase in apoptosis was observed. 27 In contrast with in vitro data reported in CML, STI571 failed to enhance the cytotoxicity of either carboplatin or etoposide when coadministered with these agents. 27 No data are available concerning the efficacy of STI571 in in vivo xenografted human SCLC tumors or on the therapeutic potential of combined administration of chemotherapy and imatinib in these tumors. We therefore investigated the therapeutic efficacy of STI571, alone or combined with chemotherapeutic agents, on various human SCLC cells or tumors xenografted into nude mice. We found that STI571 induced tumor growth inhibition to a variable extent that was not dependent on c-kit expression level, and a synergistic efficacy of concomitant chemotherapy was observed, associated with increased toxicity. Material and methods Cell lines, culture conditions and quantification of proliferation and apoptosisThe SCLC6 human small cell lung cancer cell line was obtained from tumor that was previously xenografted into nude mice. 39 Transplanted tumors were dissected and suspended in culture medium. After filtration, cells were grown in DMEM (Sigma, St. Louis, MO) supplemented with 10% FCS (Dutscher, Brumath, France), and Penicillin G (10 2 IU/ml) ϩ streptomycin (50 g/ml; Sigma). Cells were cultured in medium containing stem cell factor (SCF, Amgen, Nevilly sur Seine, France) or medium alone in the presence or absence of STI571 (Novartis, Basel, Switzerland) and/or etoposide (Pierre Fabre, Boulogne, France) or topotecan (GlaxoSmit...

Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets

“…This rate became even higher (about 75%) with a 10-μmol dose. Such concentrations are certainly higher than those used for chronic myeloid leukemia; however, they are similar to those proposed for some categories of solid tumors (e.g., Leydig cell tumor and small cell carcinoma of the lung) (55,56). Notably, imatinib exerted a limited effect on the viability of normal lymphocytes, whereas daunorubicin resulted in a significant reduction in their vitality (data not shown).…”

Inhibition of the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway but not the MEK/ERK Pathway Attenuates Laminin-Mediated Small Cell Lung Cancer Cellular Survival and Resistance to Imatinib Mesylate or Chemotherapy

“…Expression of the other known target RTK for imatinib, PDGFRs, in SCLC cells was not observed in our study but may have greater importance in stromal cells. Moreover, other relevant unknown targets may exist for imatinib because imatinib can inhibit the growth of SCLC cells in vivo that do not express c-Kit or PDGFR (42).…”

Activation of Abl Family Kinases in Solid Tumors

“…85,98 Interestingly, unlike in nontransformed cells, inhibition of active c-Abl with imatinib sensitizes these cells to a variety of chemotherapeutic agents, indicating that active cytoplasmic c-Abl/Arg likely induces resistance rather than apoptosis in response to DNA-damaging agents. 85 Imatinib also sensitizes CML, head and neck, ovarian, colon, non-small cell and small cell lung cancer, glioma, and neuroblastoma cell lines to chemotherapeutic agents [141][142][143][144][145][146][147][148][149][150] ; however, the targets of imatinib were not identified in these reports. In contrast, Le and colleagues 129 screened an siRNA kinase library to identify kinases whose decreased expression increased paclitaxel-mediated antiproliferative effects in ovarian cancer cells and identified SFKs (Src, Fyn, Yes) as well as c-Abl and Arg.…”