RESUMEN

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.

Asunto(s)

Inhibidores de Caspasas/uso terapéutico , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Urea/análogos & derivados , Urea/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Caspasas/síntesis química , Inhibidores de Caspasas/farmacología , Descubrimiento de Drogas , Femenino , Humanos , Inmunidad Humoral/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas Sprague-Dawley , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Urea/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Leiomyosarcomas remain challenging tumors to manage and novel therapy strategies besides radiation and conventional chemotherapy are needed. Targeting angiogenesis by inhibition of vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) of the tumor vasculature with small molecules is a promising new therapy. It has been shown recently that these receptors are not only expressed on tumor endothelium but also on tumor cells themselves. Thus, we investigated the expression of members of the VEGF receptor (VEGFR) family and corresponding growth factors in leiomyosarcoma tissue specimens and in the leiomyosarcoma cell lines SK-LMS-1 and SK-UT-1. We evaluated the influence of the VEGFR inhibitor PTK787/ZK222584 (PTK787) on cell growth, migration, apoptosis and phosphorylation of intracellular signalling molecules. In human leiomyosarcoma tissue specimens VEGFR­1/-2 and platelet-derived growth factor receptor (PDGFR-ß) were strongly expressed. Both leiomyosarcoma cell lines expressed VEGFR­1/-3 and PDGFR-ß but VEGFR-2 protein expression was positive only in SK-UT-1. SK-LMS-1 and SK-UT-1 cells secreted high and low amounts of VEGF-A, respectively, whereas PDGF-BB secretion was similar in both cell lines. Application of PTK787 led to partial inhibition of PDGF-BB-activated AKT/p90RSK and ERK1/2 signalling pathways. In contrast, protein phosphorylation was not affected by PTK787 in VEGF-A-treated cells. PTK787 turned out to inhibit cell migration even though no effects were observed upon stimulation with VEGF-A or PDGF-BB. In line, cell growth in leiomyosarcoma cell lines remained unchanged upon PTK787 treatment alone and with subsequent VEGF-A- or PDGF-BB-stimulation. However, VEGF-A, but not PDGF-BB-treated cells showed increased cell death upon PTK787 treatment. VEGFR family members are expressed in leiomyosarcomas in vivo and in vitro. Upon receptor stimulation, PTK787 is able to inhibit subsequent phosphorylation events and influences cell survival but not metabolic activity and migration. Thus, the inhibitor is possibly an additional option in the treatment of leiomyosarcomas.

Asunto(s)

Leiomiosarcoma/tratamiento farmacológico , Neovascularización Patológica/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Inhibidores de la Angiogénesis/administración & dosificación , Becaplermina , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Neovascularización Patológica/tratamiento farmacológico , Ftalazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-sis/administración & dosificación , Proteínas Proto-Oncogénicas c-sis/biosíntesis , Piridinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores

RESUMEN

Imatinib, nilotinib and dasatinib are protein kinase inhibitors which target the tyrosine kinase activity of the Breakpoint Cluster Region-Abelson kinase (BCR-ABL) and are used to treat chronic myelogenous leukemia. Recently, using a chemical proteomics approach another tyrosine kinase, the collagen receptor Discoidin Domain Receptor1 (DDR1) has also been identified as a potential target of these compounds. To further investigate the interaction of imatinib, nilotinib and dasatinib with DDR1 kinase we cloned and expressed human DDR1 and developed biochemical and cellular functional assays to assess their activity against DDR1 and the related receptor tyrosine kinase Discoidin Domain Receptor2 (DDR2). Our studies demonstrate that all 3 compounds are potent inhibitors of the kinase activity of both DDR1 and DDR2. In order to investigate the question of selectivity among DDR1, DDR2 and other tyrosine kinases we have aligned DDR1 and DDR2 protein sequences to other closely related members of the receptor tyrosine kinase family such as Muscle Specific Kinase (MUSK), insulin receptor (INSR), Abelson kinase (c-ABL), and the stem cell factor receptor (c-KIT) and have built homology models for the DDR1 and DDR2 kinase domains. In spite of high similarity among these kinases we show that there are differences within the ATP-phosphate binding loop (P-loop), which could be exploited to obtain kinase selective compounds. Furthermore, the potent DDR1 and DDR2 inhibitory activity of imatinib, nilotinib and dasatinib may have therapeutic implications in a number of inflammatory, fibrotic and neoplastic diseases.

Asunto(s)

Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Receptores Mitogénicos/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Benzamidas , Línea Celular , Clonación Molecular , Colágeno/metabolismo , Dasatinib , Receptor con Dominio Discoidina 1 , Receptores con Dominio Discoidina , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Modelos Moleculares , Piperazinas/farmacología , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Mitogénicos/metabolismo , Homología Estructural de Proteína , Tiazoles/farmacología

RESUMEN

AIMS: Coxsackievirus B3 (CVB3)-induced chronic myocarditis in mice is accompanied by severe fibrosis and by sustained elevation of platelet-derived growth factor (PDGF)-A, -B, and -C levels in the cardiac tissue. To test if PDGF stimulation of resident fibroblasts causally contributes to fibrosis, we employed inhibition of PDGF receptor signalling with the orally available kinase inhibitor Imatinib. METHODS AND RESULTS: Chronic myocarditis was induced by CVB3 infection of major histocompatibility complex (MHC) class II knockout (B6Aa(0)/Aa(0)) mice. The mice were treated with 100 mg/kg Imatinib or vehicle, respectively, twice daily for 34 days. Expression of PDGF-C and of inflammatory cytokines were analysed by semi-quantitative RT-PCR. PDGFalpha receptor phosphorylation was detected by immunoblotting of cardiac tissue extracts and in situ by immunohistochemistry. Fibrosis formation was analysed by Sirius-Red staining and hydroxyproline (HP) determination. Fibronectin, and tenascin expression was analysed by RT-PCR and immunohistochemistry. Matrix metalloproteinase (MMP) activity was assessed with collagen, synthetic peptides, and gelatine as substrates. Imatinib significantly inhibited the myocarditis-related PDGFalpha receptor activation in the heart tissue. The virus titres in the hearts, inflammatory infiltrations, and elevated PDGF levels were unaffected by the Imatinib treatment. A significant attenuation of fibrosis occurred in Imatinib-treated animals. The Sirius Red-stained fibrotic area was reduced from 5.30 +/- 0.50 to 3.21 +/- 0.35%, and the HP content was reduced from 362 +/- 43 to 238 +/- 32 microMol/10 mg dry weight vs. 190 +/- 27 in uninfected controls. The expression of fibronectin, EIIIA+ fibronectin, and tenascin C were likewise reduced. The diminished matrix protein deposition was not caused by elevated MMP activity, since MMP activity was not changed or even reduced under Imatinib. CONCLUSION: The data suggest a causal role for elevated PDGF expression and PDGF receptor activity in the pathogenesis of cardiac fibrosis.

Asunto(s)

Infecciones por Coxsackievirus/complicaciones , Enterovirus Humano B , Miocarditis/tratamiento farmacológico , Miocarditis/virología , Miocardio/patología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Benzamidas , Modelos Animales de Enfermedad , Fibrosis , Corazón/efectos de los fármacos , Corazón/virología , Mesilato de Imatinib , Linfocinas/metabolismo , Masculino , Ratones , Ratones Noqueados , Miocarditis/patología , Miocardio/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

PURPOSE: Insulin-like growth factor-I (IGF-I) is a potent growth factor for small cell lung cancer (SCLC) in both the autocrine and endocrine context. It also inhibits chemotherapy-induced apoptosis through activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and we have previously shown that inhibition of this signaling pathway enhances sensitivity of SCLC cell lines to chemotherapy. The purpose of this study was to determine whether the novel IGF-I receptor (IGF-IR) kinase inhibitor, NVP-ADW742, sensitizes SCLC cell lines to etoposide and carboplatin, which are commonly used in the treatment of SCLC. EXPERIMENTAL DESIGN: Cell growth in the presence of various combinations of NVP-ADW742, imatinib (STI571; Gleevec/Glivec), and chemotherapeutic agents was monitored using a 3-(4,5 dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and analyzed using the Chou-Talalay multiple-drug-effect equation. Induction of apoptosis was assessed using terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) and Western blot analysis of procaspase 3 and poly(ADP-ribose)polymerase cleavage. IGF-I-induced vascular endothelial cell growth factor expression was monitored by Northern blot and ELISA. RESULTS: NVP-ADW742 synergistically enhanced sensitivity of multiple SCLC cell lines to etoposide and carboplatin. Maximal enhancement occurred at concentrations of NVP-ADW742 that eliminated basal PI3K-Akt activity in individual cell lines. In the WBA cell line, in which the c-Kit receptor tyrosine kinase is partly responsible for basal PI3K-Akt activity, the combination of NVP-ADW742 and imatinib was superior to NVP-ADW742 alone in sensitizing the cells to etoposide. Enhancement of the sensitivity of SCLC cell lines to etoposide, as determined by MTT assay, correlated closely with sensitization to the induction of apoptosis as measured by TUNEL and caspase activation assays. Treatment with NVP-ADW742 also eliminated IGF-I-mediated expression of vascular endothelial cell growth factor, suggesting that in addition to enhancing sensitivity of SCLC to chemotherapy, this kinase inhibitor could potentially inhibit angiogenesis in vivo. CONCLUSIONS: Inhibition of IGF-IR signaling synergistically enhances the sensitivity of SCLC to etoposide and carboplatin. This enhancement in sensitivity to chemotherapy tightly correlates with inhibition of PI3K-Akt activation. Future SCLC clinical trials incorporating IGF-IR inhibitors alone or in combination with other kinase inhibitors should include assessment of PI3K-Akt activity as a pharmacodynamic end-point.

Asunto(s)

Carboplatino/farmacología , Etopósido/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/patología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Etiquetado Corte-Fin in Situ , Factor I del Crecimiento Similar a la Insulina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor IGF Tipo 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-alpha (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription-polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.

Asunto(s)

Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/química , Benzamidas , Resistencia a Antineoplásicos , Humanos , Mesilato de Imatinib , Piperazinas/química , Pirimidinas/química

RESUMEN

Stem cell factor (SCF)/Kit and insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) autocrine loops play a prominent role in the growth of small cell lung cancer (SCLC). Previous data suggested that IGF-I protects cells from apoptosis induced by STI571, an efficient inhibitor of Kit signal transduction, by activating the critical phosphatidylinositol 3-kinase-Akt pathway. To determine if inhibition of IGF-IR signaling would be therapeutically relevant in SCLC, the activity of a novel kinase inhibitor of IGF-IR, NVP-ADW742 (Novartis Pharma AG, Basel, Switzerland), was characterized. Pretreatment of the H526 cell line with NVP-ADW742 inhibited IGF-IR signaling and growth with IC(50) values between 0.1 and 0.4 micro M. SCF-mediated Kit phosphorylation and Akt activation were inhibited with IC(50) values in the 1-5 micro M range. However, NVP-ADW742 affected neither hepatocyte growth factor-mediated Akt activation nor activity of constitutively active Akt. The therapeutic potential of NVP-ADW742 was assessed by determining its effect on growth of several SCLC cell lines in serum. These studies clearly delineated two populations of cell lines as determined by differential sensitivity to NVP-ADW742. One population, which lacks active SCF/Kit autocrine loops, was inhibited with IC(50) values between 0.1 and 0.5 micro M. A second population, which has active SCF/Kit autocrine loops, was inhibited with IC(50) values in the 4-7 micro M range. When these cell lines were treated with a combination of STI571 and NVP-ADW742, no advantage was seen in the former group, whereas, in the latter group, a clearly synergistic response to the combination was seen when growth, apoptosis, or Akt activation was assessed. These data demonstrate that NVP-ADW742 is a potent and selective IGF-IR kinase inhibitor that can efficiently inhibit the growth of cells that are highly dependent on IGF-I signaling. However, for optimal growth inhibition of SCLC cells with an active SCF/Kit autocrine loop, a combination of a Kit inhibitor (STI571) and an IGF-IR inhibitor (NVP-ADW742) appears to be necessary. These observations suggest that, in tumors in which critical signal transduction pathways can be activated by alternative receptors, optimal therapy may require inhibition of multiple receptors.

Asunto(s)

Antineoplásicos/farmacología , Carcinoma de Células Pequeñas/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Neoplasias Pulmonares/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Factor de Células Madre/farmacología , Benzamidas , División Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sustancias de Crecimiento/farmacología , Humanos , Mesilato de Imatinib , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/fisiología , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor IGF Tipo 1/metabolismo , Suero , Transducción de Señal/efectos de los fármacos , Factor de Células Madre/fisiología

RESUMEN

Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [(14)C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Camptotecina/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Piperazinas/farmacología , Pirimidinas/farmacología , Topotecan/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antineoplásicos/farmacología , Benzamidas , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Camptotecina/análogos & derivados , Línea Celular Tumoral , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Humanos , Mesilato de Imatinib , Irinotecán , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Topotecan/farmacocinética

RESUMEN

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.

Asunto(s)

Linfoma de Burkitt/enzimología , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Familia-src Quinasas/fisiología , Animales , Benzamidas , Linfoma de Burkitt/patología , División Celular/efectos de los fármacos , Quimioterapia Combinada , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Piperazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/fisiología , Proteínas Proto-Oncogénicas c-hck , Pirimidinas/farmacología , Pirroles/farmacología , Familia-src Quinasas/antagonistas & inhibidores

RESUMEN

BACKGROUND: Platelet-derived growth factor (PDGF) antagonists have demonstrated beneficial effects on neointima formation, but in studies using PDGF inhibitors and extended follow-up, the lesions reoccur. These findings implicate a need to combine targeting of PDGF with other strategies. Stimulation of reendothelialization by treatment with endothelial cell mitogens of the vascular endothelial growth factor (VEGF) family counteracts restenosis, but there are also concerns regarding the durability of the effect with this approach. METHODS AND RESULTS: To explore whether a combined use of PDGF antagonist and stimulation of reendothelialization confers better results than each therapy alone, we combined systemic administration of imatinib mesylate (STI571/Gleevec, 10 mg/kg(-1) per d(-1)), a tyrosine kinase inhibitor with activity against PDGF receptors, with local intravascular adenovirus-mediated VEGF-C gene transfer (1.15x10(10) pfu) in cholesterol-fed, balloon-injured rabbits. Throughout the course of the STI571 therapy, the circulating concentrations were able to suppress PDGF receptor phosphorylation. At 3 weeks, the treatment with STI571 led to a transient decrease in intralesion macrophages and to an increase in intimal smooth muscle cell apoptosis. VEGF-C application reduced neointima formation and accelerated reendothelialization. However, none of the therapies alone reduced intimal thickening at a 6-week time point, whereas the combined treatment led to a persistent reduction (55% versus control) in lesion size at this time point. CONCLUSIONS: Our study provides one of the first successful examples of gene therapy combined with a pharmacological treatment to modulate 2 distinct ligand-receptor signaling systems and suggests combination of local VEGF-C gene therapy with systemic inhibition of PDGF signaling as a novel principle to prevent intimal hyperplasia after vascular manipulations.

Asunto(s)

Inhibidores Enzimáticos/uso terapéutico , Hipercolesterolemia/terapia , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Túnica Íntima/patología , Factor C de Crecimiento Endotelial Vascular/genética , Adenoviridae/genética , Administración Oral , Animales , Arterias , Benzamidas , División Celular/efectos de los fármacos , Movimiento Celular , Terapia Combinada , Endotelio Vascular/patología , Inhibidores Enzimáticos/administración & dosificación , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/patología , Mesilato de Imatinib , Macrófagos/inmunología , Músculo Liso Vascular/patología , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Conejos , Túnica Íntima/citología , Túnica Íntima/efectos de los fármacos , Túnica Media/patología

RESUMEN

PURPOSE: The purpose is to investigate whether STI571, through platelet-derived growth factor receptor inhibition, enhances the therapeutic response to the chemotherapeutic drug epothilone B (EPO906) and, if so, to analyze the mechanism(s) underlying the effect. EXPERIMENTAL DESIGN: SCID mice with s.c. human anaplastic thyroid carcinomas were treated with different doses of EPO906 alone or in combination with STI571 and with different timing of STI571 and EPO906 administration. Tumor growth, tumor interstitial fluid pressure (IFP), and uptake of EPO906 in tumors and normal organs were monitored. RESULTS: STI571 potentiated the therapeutic effect of EPO906. Tumors subjected to combination treatment were >40% smaller than those subjected to monotreatment with EPO906. The improved efficacy was matched by reduced tumor IFP and a 3-fold increase in the tumor levels of EPO906. No significant increase of EPO906 levels was seen in liver, kidney, or the intestinal tract. Cotreatment did not reduce the tolerability of EPO906, as determined by measuring body weight throughout treatment. STI571-induced reduction in tumor IFP and increase in tumor uptake required a minimum of three daily doses of STI571 and was not observed 3 days after last treatment with STI571. The enhancement of EPO906 therapeutic efficacy was only observed when STI571 was scheduled in a manner associated with reduced tumor IFP and increased tumor uptake of EPO906. CONCLUSIONS: We conclude that STI571 increases the therapeutic index of EPO906 by selectively increasing the EPO906 uptake in tumors. The correlations between STI571 effects on tumor IFP and tumor drug uptake of EPO906 suggest a causal relationship between these phenomena. The study thus validates STI571 for combination treatment to enhance the therapeutic index of EPO906 in particular and, possibly, of chemotherapeutics in general.

Asunto(s)

Epotilonas/farmacocinética , Piperazinas/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/farmacología , Benzamidas , División Celular , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Cinética , Ratones , Ratones SCID , Trasplante de Neoplasias , Neoplasias de la Tiroides/patología , Factores de Tiempo

RESUMEN

BACKGROUND: Crosstalk between pro-inflammatory cytokines and platelet-derived growth factor (PDGF) regulates smooth-muscle-cell proliferation in cardiac-allograft arteriosclerosis. In this study, we tested the effect of STI 571, a novel orally active protein tyrosine kinase (PTK) inhibitor selective for PDGF receptor (PDGF-R) on transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. METHODS: Cardiac allografts were transplanted heterotopically from Dutch Belted to New Zealand White rabbits. A 0.5% cholesterol diet was begun 4 days before transplantation. Recipients received STI 571 5 mg/kg per day or vehicle intraperitoneally throughout the study period of 6 weeks. Cyclosporine A was given as background immunosuppression. RESULTS: In cardiac allografts of vehicle-treated rabbits, 76.2+/-2.1% of medium-sized arteries were affected by intimal thickening, and the percentage of arterial occlusion was 45.0+/-5.0%. Treatment with STI 571 reduced the incidence of affected medium-sized arteries to 41.2+/-8.1% (P <0.05) and the arterial occlusion to 27.6+/-5.0% ( P<0.05). In addition, we observed that STI 571 treatment reduced intimal lesion formation in proximal ascending aorta of transplanted hearts from 72.3+/-19.9 to 12.7+/-1.9 microm ( P<0.05). Our results also show that STI 571 significantly inhibited accelerated arteriosclerosis in medium-sized arteries of recipients' own hearts. CONCLUSIONS: The results of the present study suggest that PDGF-R activation may regulate the development of transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. Thus, PTK inhibitors may provide new strategies for prevention of these fibroproliferative vascular disorders.

Asunto(s)

Enfermedades de la Aorta/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Trasplante de Corazón , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Aorta Torácica , Enfermedades de la Aorta/epidemiología , Enfermedades de la Aorta/prevención & control , Benzamidas , Colesterol en la Dieta/sangre , Colesterol en la Dieta/farmacología , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/prevención & control , Femenino , Supervivencia de Injerto/efectos de los fármacos , Hipercolesterolemia/tratamiento farmacológico , Mesilato de Imatinib , Incidencia , Macrófagos/efectos de los fármacos , Piperazinas/farmacología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Pirimidinas/farmacología , Conejos , Trasplante Homólogo

RESUMEN

The leukemogenic tyrosine kinase Bcr-Abl contains a highly conserved inhibitor-binding pocket (IBP), which serves as a binding site for imatinib mesylate. Mutations at the IBP may lead to resistance of the Abl kinase against imatinib mesylate. To examine the mechanisms of imatinib mesylate binding and resistance in more detail, we created several point mutations at amino acid positions 315 and 380 of Abl, blocking the access to the IBP and rendering Bcr-Abl imatinib mesylate-resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (Asp276Ser/Glu279Ser) also led to imatinib mesylate resistance, suggesting that the inhibitor required inactivation of the kinase prior to binding. These Bcr-Abl mutants were then used to evaluate the binding mode and specificity of 2 compounds, PP1 and CGP76030, originally characterized as Src kinase inhibitors. Both compounds inhibited Bcr-Abl in a concentration-dependent manner by overlapping binding modes. However, in contrast to imatinib mesylate, PP1 and CGP76030 blocked cell growth and survival in cells expressing various inhibitor-resistant Abl mutants. Studies on the potential signaling mechanisms demonstrated that in cells expressing inhibitor-resistant Bcr-Abl mutants, PP1 and CGP76030 inhibited the activity of Src family tyrosine kinases and Akt but not signal transducer and activator of transcription-5 (STAT5) and JUN kinase (Jnk). The results suggest that the use of Src kinase inhibitors is a potential strategy to prevent or overcome clonal evolution of imatinib mesylate resistance in Bcr-Abl(+) leukemia.

Asunto(s)

Resistencia a Antineoplásicos/genética , Inhibidores Enzimáticos/farmacología , Leucemia/tratamiento farmacológico , Proteínas Oncogénicas v-abl/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Benzamidas , Sitios de Unión/genética , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/metabolismo , Proteínas de Fusión bcr-abl/química , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib , Leucemia/enzimología , Leucemia/patología , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Piperazinas , Conformación Proteica , Pirroles/farmacología

RESUMEN

A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism.

Asunto(s)

Antineoplásicos/farmacología , Factores de Crecimiento Endotelial/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Linfocinas/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacología , Animales , Benzamidas , Western Blotting , División Celular , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Densitometría , Relación Dosis-Respuesta a Droga , Endotelio Vascular/metabolismo , Humanos , Mesilato de Imatinib , Interleucina-3/metabolismo , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Neovascularización Patológica , Pruebas de Precipitina , Factores de Tiempo , Transfección , Venas Umbilicales/citología , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular

RESUMEN

Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzamidas , Sinergismo Farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Fluorouracilo/farmacología , Mesilato de Imatinib , Ratones , Ratones SCID , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Paclitaxel/farmacología , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Ratas , Receptores del Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Receptores del Factor de Crecimiento Derivado de Plaquetas/fisiología , Transducción de Señal/fisiología , Células del Estroma/patología , Porcinos , Neoplasias de la Tiroides/irrigación sanguínea , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Quinasas , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Benzamidas , Ciclo Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Humanos , Mesilato de Imatinib , Ratones , Piperazinas , Inhibidores de Proteínas Quinasas , Proteínas Quinasas/metabolismo , Proteínas Quinasas/fisiología , Pirimidinas/uso terapéutico

RESUMEN

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

Asunto(s)

Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Pirimidinas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Animales , Benzamidas , Proteínas de Fusión bcr-abl , Humanos , Mesilato de Imatinib , Piperazinas/química , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico

RESUMEN

STI571, a selective inhibitor of Bcr-Abl, has been a successful therapeutic agent in clinical trials for chronic myelogenous leukemia. Chronic phase chronic myelogenous leukemia patients treated with STI571 have durable responses; however, most responding blast phase patients relapse despite continued therapy. Co-crystallization studies of Abl kinase and an STI571-related compound identify specific amino acid residues as critical to STI571 binding, one of which, T315, has been characterized as an acquired Thr to Ile mutation in relapsed patients. Other studies, however, suggest that mutations other than these predicted contact points are capable of conferring STI571 resistance in relapsed patients. Using a variety of models of STI571 binding to the Abl kinase, we have performed an extensive mutational analysis of sites that might alter the sensitivity of the Abl kinase to STI571. Although mutation of many of the predicted contact points between Abl and STI571 result in a kinase-inactive protein, additional mutations that render the Abl kinase less sensitive to STI571 demonstrate a broad range of possibilities for clinical resistance that are now becoming evident.

Asunto(s)

Adenosina Trifosfato/metabolismo , Piperazinas/farmacología , Mutación Puntual , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Pirimidinas/farmacología , Benzamidas , Sitios de Unión , Clonación Molecular , Inhibidores Enzimáticos/farmacología , Humanos , Mesilato de Imatinib , Cinética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Modelos Moleculares , Conformación Proteica , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Sensibilidad y Especificidad , Especificidad por Sustrato

RESUMEN

BACKGROUND: Bcr-Abl, a constitutively activated tyrosine kinase, is a product of the Philadelphia chromosome (Ph) translocation t(9;22), present in nearly all cases of chronic myeloid leukemia (CML) and in about 20% of cases with acute lymphoblastic leukemia. CML, a myeloproliferative disorder, progresses through three phases--chronic phase, accelerated phase and blast crisis. Current therapies include drug regimens such as interferon alpha, hydroxyurea, busulfan or allogeneic bone marrow transplantation, the only curative treatment for CML, which is, however, limited to younger patients with a suitable donor. INHIBITION OF BCR-ABL AS EFFECTIVE AND SELECTIVE TREATMENT IN CML: In vitro studies and studies in animal models have shown, that Bcr-Abl is the molecular cause CML. Therefore inhibition of the Bcr-Abl tyrosine kinase is expected to be an effective and selective treatment modality for CML. STI571 was shown to be a competitive inhibitor at the ATP-binding site of the Bcr-Abl tyrosine kinase, the platelet-derived growth factor receptor and c-kit tyrosine kinases. It shows effects on proliferation and survival of Bcr-Abl-expressing cells without affecting normal cells or Ph-negative leukemic cells. DRUG RESISTANCE TO STI571: Several mechanisms of resistance have been identified from in vitro studies with Bcr-Abl-positive cell lines. Mechanisms include amplification or overexpression of Bcr-Abl or an increased expression of P-gly-coprotein. In a mouse model the binding of STI571 to acidic alpha 1 glycoprotein (AAG) has been proposed to be involved in the development of STI571 resistance. Recent studies with clinical samples from resistant patients have shown that point mutations in the kinase domain of Bcr-Abl play a role in the development of resistance to STI571. CONCLUSIONS: STI571 is a promising example of a moleculary targeted therapy directed towards the molecular cause of CML. To maximize the therapeutic value and to avoid the induction of resistance, a combination of the drug with other chemotherapies should be considered. According to its pharmacological profile, STI571 could also be useful in the treatment of tumors with deregulated PDGF receptor or c-kit signaling, e.g., in chronic myelomonocytic leukemia with a t(5;12) chromosomal translocation or in cases with gastrointestinal stromal tumors (GIST). STI571 shows a new paradigm in the development of new targeted therapies for the treatment of malignant diseases.

Asunto(s)

Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Animales , Benzamidas , Proteínas de Fusión bcr-abl , Humanos , Mesilato de Imatinib

RESUMEN

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.

Asunto(s)

Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Neoplasias de Tejido Conjuntivo/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Células del Estroma , Benzamidas , Humanos , Mesilato de Imatinib , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores