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1.
Clin Cancer Res ; 21(11): 2415-7, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26034217

RESUMO

The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials.


Assuntos
Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirróis/uso terapêutico , Aniversários e Eventos Especiais , História do Século XXI , Humanos , Indóis/história , Neoplasias/história , Pirróis/história , Sunitinibe
2.
BMC Nephrol ; 15: 81, 2014 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-24884838

RESUMO

BACKGROUND: AMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis. METHODS: AMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the "1K1C" model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively). RESULTS: Administration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals. CONCLUSIONS: As a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.


Assuntos
Calcimiméticos/administração & dosagem , Modelos Animais de Doenças , Naftalenos/administração & dosagem , Peptídeos/administração & dosagem , Receptores de Detecção de Cálcio/agonistas , Uremia/tratamento farmacológico , Animais , Cinacalcete , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento , Uremia/fisiopatologia
3.
Expert Rev Vaccines ; 12(9): 1047-60, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24053398

RESUMO

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and the elderly. Despite its relatively low degree of antigenic variation, it causes frequent reinfection throughout life. Clinical manifestations of RSV disease and the immune response to infection differ in infants and the elderly, suggesting that vaccines designed to protect these two populations may require different attributes. Here, the authors describe the translational approach of utilizing data from epidemiology studies performed in these populations, the use of RSV diagnostics in clinical practice, lessons learned from previous vaccine clinical trials and the success of palivizumab in prevention of RSV disease in premature and high-risk infants to aid the development of safe and effective RSV vaccines.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antivirais/administração & dosagem , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/isolamento & purificação , Vírus Sinciciais Respiratórios/imunologia , Descoberta de Drogas/tendências , Humanos , Palivizumab , Infecções por Vírus Respiratório Sincicial/prevenção & controle
4.
J Pharmacol Exp Ther ; 346(2): 229-40, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23674604

RESUMO

A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.


Assuntos
Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Receptores de Detecção de Cálcio/agonistas , Animais , Feminino , Fator de Crescimento de Fibroblastos 23 , Células HEK293 , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Rim/fisiopatologia , Masculino , Nefrectomia , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/sangue , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Diálise Renal/efeitos adversos , Distribuição Tecidual , Uremia/tratamento farmacológico , Uremia/etiologia
5.
Antimicrob Agents Chemother ; 50(10): 3260-8, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17005803

RESUMO

The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.


Assuntos
Antivirais/farmacologia , Carbamatos/farmacologia , Modelos Animais de Doenças , Hepacivirus/efeitos dos fármacos , Interferon-alfa/farmacologia , Compostos Macrocíclicos/farmacologia , Quinolinas/farmacologia , Tiazóis/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Linhagem Celular Tumoral/transplante , Avaliação Pré-Clínica de Medicamentos , Feminino , Hepatite C/virologia , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico
6.
Mol Cancer Ther ; 5(7): 1774-82, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16891463

RESUMO

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-beta, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Morfolinas/química , Morfolinas/farmacologia , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Células Tumorais Cultivadas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Clin Cancer Res ; 12(16): 4908-15, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16914579

RESUMO

PURPOSE: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model. EXPERIMENTAL DESIGN: We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C). The antimyeloma activity of CHIR-258 was evaluated at doses that inhibited FGFR3 signaling in vivo in this FGFR3-driven animal model. RESULTS: Noninvasive bioluminescence imaging detected MM lesions in nearly all mice injected with KMS-11-luc cells, which were mainly localized in the spine, skull, and pelvis, resulting in frequent development of paralysis. Daily oral administration of CHIR-258 at doses that inhibited FGFR3 signaling in KMS-11-luc tumors in vivo resulted in a significant inhibition of KMS-11-luc tumor growth, which translated into a significant improvement in animal survival. CONCLUSIONS: Our data provide a relevant preclinical basis for clinical trials of CHIR-258 in FGFR3-positive MM patients.


Assuntos
Benzimidazóis/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Quinolonas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos SCID , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mieloma Múltiplo/enzimologia , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/sangue , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mol Cancer Ther ; 5(5): 1280-9, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16731761

RESUMO

Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PDGFRbeta and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Indutores da Angiogênese/metabolismo , Indutores da Angiogênese/farmacologia , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas , Feminino , Células HT29 , Humanos , Mesilato de Imatinib , Indóis/metabolismo , Indóis/uso terapêutico , Camundongos , Camundongos Endogâmicos , Piperazinas/metabolismo , Piperazinas/farmacologia , Propionatos/metabolismo , Propionatos/farmacologia , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirróis/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sunitinibe , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Res ; 63(21): 7345-55, 2003 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-14612533

RESUMO

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the development and progression of several human cancers and are attractive targets for cancer therapy. PHA-665752 was identified as a small molecule, ATP-competitive, active-site inhibitor of the catalytic activity of c-Met kinase (K(i) 4 nM). PHA-665752 also exhibited >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. In cellular studies, PHA-665752 potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells. In addition, PHA-665752 inhibited HGF-stimulated or constitutive phosphorylation of mediators of downstream signal transduction of c-Met, including Gab-1, extracellular regulated kinase, Akt, signal transducer and activator of transcription 3, phospholipase C gamma, and focal adhesion kinase, in multiple tumor cell lines in a pattern correlating to the phenotypic response of a given tumor cell. In in vivo studies, a single dose of PHA-665752 inhibited c-Met phosphorylation in tumor xenografts for up to 12 h. Inhibition of c-Met phosphorylation was associated with dose-dependent tumor growth inhibition/growth delay over a repeated administration schedule at well-tolerated doses. Interestingly, potent cytoreductive activity was demonstrated in a gastric carcinoma xenograft model. Collectively, these results demonstrate the feasibility of selectively targeting c-Met with ATP-competitive small-molecules and suggest the therapeutic potential of targeting c-Met in human cancers.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Sulfonas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Rim/enzimologia , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Células NIH 3T3 , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Pharmacol Exp Ther ; 307(2): 476-80, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12966161

RESUMO

Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide), an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans.


Assuntos
Inibidores Enzimáticos/farmacologia , Cor de Cabelo/efeitos dos fármacos , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Feminino , Cor de Cabelo/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Sunitinibe
11.
Clin Cancer Res ; 9(7): 2755-68, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12855656

RESUMO

PURPOSE: The purpose of the following study was to investigate the safety and efficacy of the novel multitargeted indolinone receptor tyrosine kinase (RTK) inhibitor, SU11654, using a canine model of spontaneous tumors. This p.o. bioavailable compound exhibits potent inhibitory activity against members of the split kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Kit, and Flt-3, resulting in both direct antitumor and antiangiogenic activity. EXPERIMENTAL DESIGN: This was a Phase I trial in which successive cohorts of dogs with spontaneous tumors that had failed standard treatment regimens received escalating doses of SU11654 as oral therapy. Pharmacokinetics, toxicity, and tumor response were assessed. RESULTS: Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors (n = 11), mixed mammary carcinomas (n = 2), soft tissue sarcomas (n = 2), and multiple myeloma (n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57). CONCLUSIONS: This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.


Assuntos
Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Pirróis/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Indóis/administração & dosagem , Concentração Inibidora 50 , Masculino , Modelos Químicos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Tempo , Tomografia Computadorizada por Raios X
12.
Mol Cancer Ther ; 2(5): 461-9, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12748308

RESUMO

The Src family kinases (SFKs) Src and Yes are believed to play critical roles in tumor growth, angiogenesis, invasion, and dissemination. Using a panel of highly selective and structurally diverse Src inhibitors, we found that phosphorylation of signal transducer and activator of transcription 3 [STAT3 (Y705)] and focal adhesion kinase [FAK (Y861)] was SFK dependent in cultured human colon, breast, lung, and ovarian tumor cells. These findings were reproduced in vivo in target modulation studies using tumors derived from fibroblasts overexpressing activated Src. Additionally, treatment of mice with multiple Src inhibitors resulted in inhibition of phosphorylation of FAK (Y861) and of a putative Src autophosphorylation epitope (Y419) in HT-29 human colon tumor xenografts. Next we pharmacologically examined the requirement for SFKs in asynchronous proliferation of human tumor cells. At concentrations sufficient to selectively inhibit Src, structurally diverse Src inhibitors inhibited growth of cultured human colon, breast, and lung cells on plastic under low serum conditions. In addition, these compounds inhibited anchorage-independent growth of HT-29 human colon tumor cells in soft agar. The role of SFK activity in vascular endothelial growth factor signaling was also evaluated. Inhibition of SFK signaling using structurally distinct Src inhibitors resulted in complete inhibition of vascular endothelial growth factor-dependent vascular permeability in vivo. These data demonstrate that STAT3 (Y705) and FAK (Y861) phosphoepitopes are SFK-dependent in tumor cells and reveal a requirement for SFK function in tumor cell proliferation and vascular permeability.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neoplasias Experimentais/patologia , Proteínas Tirosina Quinases/metabolismo , Transativadores/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Quinases da Família src/fisiologia , Animais , Apoptose , Adesão Celular/efeitos dos fármacos , Divisão Celular , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Fosforilação , Fator de Transcrição STAT3 , Transdução de Sinais , Células Tumorais Cultivadas , Tirosina/metabolismo , Quinases da Família src/antagonistas & inibidores
13.
Clin Cancer Res ; 9(1): 327-37, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12538485

RESUMO

One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo, SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor beta phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50-100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo. Constant inhibition of VEGFR2 and PDGF receptor beta phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Fosforilação , Sunitinibe , Fatores de Tempo , Células Tumorais Cultivadas
14.
Antimicrob Agents Chemother ; 46(12): 3809-16, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12435681

RESUMO

Oseltamivir carboxylate is a potent and specific inhibitor of influenza neuraminidase (NA). An influenza A/H1N1 variant selected in vitro with reduced susceptibility to oseltamivir carboxylate contains a His274Tyr mutation. To understand the mechanism by which a His274Tyr mutation gives rise to drug resistance, we studied a series of NA variant proteins containing various substitutions at position 274. Replacement of His274 with larger side chain residues (Tyr or Phe) reduced the NA sensitivity to oseltamivir carboxylate. In contrast, replacement of His274 with smaller side chain residues (Gly, Asn, Ser, and Gln) resulted in enhanced or unchanged sensitivity to oseltamivir carboxylate. Previous studies have suggested that the slow-binding inhibition of NA by oseltamivir carboxylate is a result of the reorientation of Glu276. Loss of this slow-binding inhibition in the His274Tyr and His274Phe mutant NA but not in His274Asn, His274Gly, His274Ser, or His274Gln supports the conclusion that the conformational change of Glu276 is restricted in the His274Tyr and His274Phe mutant NA upon oseltamivir carboxylate binding. Interestingly, His274Asn, as well as His274Gly, His274Ser, and His274Gln, also displayed reduced sensitivity to zanamivir and its analogue, 4-amino-Neu5Ac2en. Substitution of His274 with Tyr in influenza A/Tokyo/3/67 (H3N2) recombinant NA did not affect the susceptibility to oseltamivir carboxylate. These data indicate that the volume occupied by the amino acid side chain at position 274 can influence the sensitivities of influenza N1 NA but not of N2 NA to both oseltamivir carboxylate and zanamivir.


Assuntos
Acetamidas/farmacologia , Antivirais/farmacologia , Vírus da Influenza A , Mutação , Neuraminidase/antagonistas & inibidores , Ácidos Siálicos/farmacologia , Guanidinas , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Vírus da Influenza A/genética , Oseltamivir , Piranos , Relação Estrutura-Atividade , Zanamivir
15.
Blood ; 100(2): 585-93, 2002 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12091352

RESUMO

Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated 3 indolinones (SU11652, SU11654, and SU11655) that act as competitive inhibitors of adenosine triphosphate binding to several members of the split kinase family of RTKs, including VEGFR, FGFR, PDGFR, and Kit. Mast cell lines expressing either wild-type (WT) Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, or a point mutation in the catalytic domain were used for these studies. All 3 indolinones inhibited phosphorylation of WT Kit in the presence of stem cell factor at concentrations as low as 0.01 microM. Autophosphorylation of both JM mutants was inhibited at 0.01 to 0.1 microM, resulting in cell cycle arrest within 24 hours, whereas autophosphorylation of the catalytic domain mutant was inhibited at 0.25 to 0.5 microM, resulting in cell death within 24 hours. poly(ADP-ribose) polymerase (PARP) cleavage was noted in all Kit mutant lines after indolinone treatment. In summary, SU11652, SU11654, and SU11655 are effective RTK inhibitors capable of disrupting the function of all forms of mutant Kit. Because the concentrations of drug necessary for receptor inhibition are readily achievable and nontoxic in vivo, these compounds may be useful in the treatment of spontaneous cancers expressing Kit mutations.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Mutação , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Sarcoma de Mastócitos/enzimologia , Sarcoma de Mastócitos/patologia , Fosforilação/efeitos dos fármacos , Estrutura Terciária de Proteína , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirróis/farmacologia , Células Tumorais Cultivadas
16.
FASEB J ; 16(7): 681-90, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11978732

RESUMO

SU6668 is a small molecule inhibitor of the angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta, and FGFR1. In mice, SU6668 treatment resulted in regression or growth arrest of all large established human tumor xenografts examined associated with loss of tumor cellularity. The events underlying loss of tumor cellularity were elucidated in detail in several tumor models. SU6668 treatment induced apoptosis in tumor microvessels within 6 h of the initiation of treatment. Dose-dependent decreases in tumor microvessel density were observed within 3 days of the first treatment. These changes were accompanied by decreased tumor cell proliferation and increased tumor cell apoptosis. Rapid increases in VEGF transcript levels were seen, consistent with the induction of tumor hypoxia. Using Western blot analyses, we determined that these in vivo antiangiogenic and proapoptotic effects of SU6668 occur at doses comparable to those required to inhibit Flk-1/KDR and PDGFRbeta phosphorylation in tumors. Potent, dose-dependent inhibition of Flk-1/KDR activity in vivo was independently demonstrated using vascular permeability as a readout. These data demonstrate that SU6668-induced inhibition of angiogenic receptor tyrosine kinase activity in vivo is associated with rapid vessel killing in tumors, leading to broad and potent antitumor effects.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Pirróis/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Apoptose , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/uso terapêutico , Cinética , Camundongos , Camundongos Nus , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/patologia , Oxindóis , Propionatos , Pirróis/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Am Soc Nephrol ; 11(3): 383-393, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10703662

RESUMO

The transport of organic anions in proximal convoluted tubules plays an essential role in the active secretion of a variety of small molecules by the kidney. In addition to other anionic substrates, the human renal organic anion transporter 1 (hOATI) is capable of transporting the nucleotide analogs adefovir and cidofovir. To investigate the involvement of hOATI in the mechanism of nephrotoxicity associated with these two clinically important antiviral agents, Chinese hamster ovary (CHO) cells were stably transfected with hOATI cDNA. The resulting CHOhOAT cells showed probenecid-sensitive and pH-dependent uptake of p-aminohippurate (Km = 15.4 FtM, V,,, ..ax = 20.6 pmol/106 cells min), a prototypical organic anion substrate. In addition, the stably expressed hOATI mediated efficient transport of adefovir (Km, = 23.8 tLM, V, a,, = 46.0 pmol/106 cells min) and cidofovir (K, = 58.0 /iM, Vt,ax = 103 pmol/106 cells * min) such that the levels of intracellular metabolites of both nucleotides were > 1 00-fold higher in CHOh OAT cells than in parental CHO. Consequently, adefovir and cidofovir were approximately 500-fold and 400-fold more cytotoxic, respectively, in CHOh OAT cells compared to CHO. The cytotoxicity of both drugs in CHOh OAT cells was markedly reduced in the presence of hOATI inhibitors. The cyclic prodrug of cidofovir, which exhibits reduced in vivo nephrotoxicity, was a poor substrate for hOATI and showed only marginally increased cytotoxicity in CHOh OAT cells. In conclusion, these studies demonstrate that hOATI plays a critical role in the organ-specific toxicity of adefovir and cidofovir, and indicates that CHOh OAT cells may represent a useful in vitro model to investigate the potential nephrotoxicity of clinically relevant organic anion agents.


Assuntos
Adenina/análogos & derivados , Antivirais/intoxicação , Proteínas de Transporte/fisiologia , Citosina/análogos & derivados , Rim/efeitos dos fármacos , Intoxicação por Organofosfatos , Organofosfonatos , Adenina/antagonistas & inibidores , Adenina/metabolismo , Adenina/farmacocinética , Adenina/intoxicação , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Proteínas de Transporte de Ânions , Antivirais/antagonistas & inibidores , Antivirais/metabolismo , Antivirais/farmacocinética , Transporte Biológico/fisiologia , Células CHO , Proteínas de Transporte/metabolismo , Cidofovir , Cricetinae , Citosina/antagonistas & inibidores , Citosina/metabolismo , Citosina/farmacocinética , Citosina/intoxicação , Humanos , Rim/citologia , Rim/metabolismo , Compostos Organofosforados/antagonistas & inibidores , Compostos Organofosforados/metabolismo , Compostos Organofosforados/farmacocinética , Probenecid/farmacologia
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