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1.
Mol Pharm ; 9(5): 1126-35, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22432738

RESUMO

The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib.


Assuntos
Ácidos Borônicos/farmacologia , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologia , Animais , Ácidos Borônicos/química , Bortezomib , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos SCID , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/química , Pirazinas/química
2.
Mol Cancer Ther ; 5(7): 1744-53, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16891460

RESUMO

CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, respectively, for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 versus 192 days, respectively; P < or = 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. x 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Carbazóis/administração & dosagem , Carcinoma/patologia , Neoplasias do Colo/patologia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Glioblastoma/patologia , Humanos , Irinotecano , Camundongos , Camundongos Nus , Metástase Neoplásica , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 64(3): 910-9, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14871820

RESUMO

Tumor-associated angiogenesis is critical for tumor growth and metastasis and is controlled by various pro- and antiangiogenic factors. The Eph family of receptor tyrosine kinases has emerged as one of the pivotal regulators of angiogenesis. Here we report that interfering with EphA signaling resulted in a pronounced inhibition of angiogenesis in ex vivo and in vivo model systems. Administration of EphA2/Fc soluble receptors inhibited, in a dose-dependent manner, microvessel formation in rat aortic ring assay, with inhibition reaching 76% at the highest dose of 5000 ng/ml. These results were further confirmed in vivo in a porcine aortic endothelial cell-vascular endothelial growth factor (VEGF)/basic fibroblast growth factor Matrigel plug assay, in which administration of EphA2/Fc soluble receptors resulted in 81% inhibition of neovascularization. The additive effects of simultaneous inhibition of VEGF receptor 2 and EphA signaling pathways in aortic ring assay and antiangiogenic efficacy of EphA2/Fc soluble receptors against VEGF/basic fibroblast growth factor-mediated neovascularization in vivo indicated a critical and nonredundant role for EphA signaling in angiogenesis. Furthermore, in two independent experiments, we demonstrated that EphA2/Fc soluble receptors strongly (by approximately 50% versus controls) suppressed growth of ASPC-1 human pancreatic tumor s.c. xenografts. Inhibition of tumor growth was due to decreased proliferation of tumor cells. In an orthotopic pancreatic ductal adenocarcinoma model in mice, suppression of EphA signaling by i.p. administration of EphA2/Fc (30 micro g/dose, three times a week for 56 days) profoundly inhibited the growth of primary tumors and the development of peritoneal, lymphatic, and hepatic metastases. These data demonstrate a critical role of EphA signaling in tumor growth and metastasis and provide a strong rationale for targeting EphA2 receptors for anticancer therapies.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Receptor EphA2/antagonistas & inibidores , Receptores Fc/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/metabolismo , Feminino , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor EphA2/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Res ; 63(17): 5559-63, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-14500395

RESUMO

All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.


Assuntos
Carbazóis/farmacologia , Carcinoma Medular/tratamento farmacológico , Indóis , Proteínas Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Carcinoma Medular/enzimologia , Carcinoma Medular/patologia , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Furanos , Inibidores do Crescimento/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasia Endócrina Múltipla Tipo 2b/genética , Mutação , Proteínas Oncogênicas/metabolismo , Fosforilação/efeitos dos fármacos , Pró-Fármacos/farmacologia , Proteínas Proto-Oncogênicas c-ret , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Res ; 63(18): 5978-91, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-14522925

RESUMO

Inhibition of the vascular endothelial growth factor VEGF-VEGF receptor (VEGF-R) kinase axes in the tumor angiogenic cascade is a promising therapeutic strategy in oncology. CEP-7055 is the fully synthetic orally active N,N-dimethyl glycine ester of CEP-5214, a C3-(isopropylmethoxy) fused pyrrolocarbazole with potent pan-VEGF-R kinase inhibitory activity. CEP-5214 demonstrates IC(50) values of 18 nM, 12 nM, and 17 nM against human VEGF-R2/KDR kinase, VEGF-R1/FLT-1 kinase, and VEGF-R3/FLT-4 kinase, respectively, in biochemical kinase assays. CEP-5214 inhibited VEGF-stimulated VEGF-R2/KDR autophosphorylation in human umbilical vein endothelial cells (HUVECs) with an IC (50) of approximately 10 nM and demonstrated an equivalent inhibition of murine FLK-1 autophosphorylation in transformed SVR endothelial cells. Evaluation of the antiangiogenic activity of CEP-5214 revealed a dose-related inhibition of microvessel growth ex vivo in rat aortic ring explant cultures and in vitro on HUVEC capillary-tube formation on Matrigel at low nanomolar concentrations. The antiangiogenic activity of CEP-5214 in these bioassays was observed in the absence of apparent cytotoxicity. Single-dose p.o. or s.c. administration of CEP-7055 or CEP-5214 to CD-1 mice at 23.8 mg/kg/dose b.i.d. resulted in a reversible inhibition of VEGF-R2/FLK-1 phosphorylation in murine lung tissues. Administration p.o. of CEP-7055 at 2.57 to 23.8 mg/kg/dose b.i.d. resulted in dose-related reductions in neovascularization in vivo in porcine aortic endothelial cell (PAEC)-VEGF/basic fibroblast growth factor-Matrigel implants in nude mice (maximum, 82% inhibition), significant reductions in granuloma formation (30%) and granuloma vascularity (42%) in a murine chronic inflammation-induced angiogenesis model, and significant and sustained (6 h) inhibition of VEGF-induced plasma extravasation in rats, with an ED(50) of 20 mg/kg/dose. Chronic p.o. administration of CEP-7055 at doses of 11.9 to 23.8 mg/kg/dose b.i.d. resulted in significant inhibition (50-90% maximum inhibition relative to controls) in the growth of a variety of established murine and human s.c. tumor xenografts in nude mice, including A375 melanomas, U251MG and U87MG glioblastomas, CALU-6 lung carcinoma, ASPC-1 pancreatic carcinoma, HT-29 and HCT-116 colon carcinomas, MCF-7 breast carcinomas, and SVR angiosarcomas. Significant antitumor efficacy was observed similarly against orthotopically implanted LNCaP human prostate carcinomas in male nude mice and orthotopically implanted renal carcinoma (RENCA) tumors in BALB/c mice, in terms of a significant reduction in the metastatic score and the extent of pulmonary metastases. These antitumor responses were associated with marked increases in tumor apoptosis, and significant reductions in intratumoral microvessel density (CD34 and Factor VIII staining) of 22-38% relative to controls depending on the specific tumor xenograft. The antitumor efficacy of chronic CEP-7055 administration was independent of initial tumor volume (in the ASPC-1 pancreatic carcinoma model) and reversible on withdrawal of treatment. Chronic p.o. administration of CEP-7055 in preclinical efficacy studies for periods of up to 65 days was well tolerated with no apparent toxicity or significant morbidity. Orally administered CEP-7055 has entered Phase I clinical trials in cancer patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/farmacocinética , Carbazóis/farmacocinética , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/enzimologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/enzimologia , Fosforilação , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Mol Cancer Ther ; 2(4): 371-82, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12700281

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.


Assuntos
Camptotecina/análogos & derivados , Camptotecina/farmacologia , Cisplatino/farmacologia , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Divisão Celular , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Irinotecano , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Temozolomida , Fatores de Tempo
7.
Curr Protoc Pharmacol ; Appendix 4: Appendix 4B, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23258596

RESUMO

This unit provides a general overview on topics related to the practical care and use of laboratory animals in biomedical research. These topics are briefly described and provide Web sites and/or research articles that can be accessed for more detailed information. While the primary focus is on the care and use of rats and mice bred for biomedical research, many of the Web sites listed provide information on other species used for this purpose.


Assuntos
Experimentação Animal/normas , Bem-Estar do Animal/normas , Animais de Laboratório , Pesquisa/normas , Anestesia/métodos , Animais , Eutanásia Animal/métodos , Camundongos , Dor , Manejo da Dor/veterinária , Ratos , Tamanho da Amostra
8.
Leuk Res ; 36(11): 1422-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22906694

RESUMO

Preclinical and clinical studies have shown that proteasome inhibitors (PIs) have anti-MM activity in combination with dexamethasone or lenalidomide. However, no data exists on the anti-MM effects of combinations involving the PI delanzomib with dexamethasone and/or lenalidomide. Herein, we show that delanzomib in combination with dexamethasone and/or lenalidomide results in superior tumor reduction and extended tumor growth delays when compared to vehicle alone, these drugs alone, or the doublet of dexamethasone and lenalidomide. The favorable results obtained from the three xenograft studies suggest that delanzomib in combination with dexamethasone and lenalidomide should be explored for the treatment of MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ácidos Borônicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Treonina/análogos & derivados , Animais , Linhagem Celular Tumoral , Dexametasona/administração & dosagem , Humanos , Lenalidomida , Camundongos , Camundongos SCID , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Treonina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Med Chem ; 55(2): 903-13, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22148921

RESUMO

A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.


Assuntos
Inibidores da Angiogênese/síntese química , Carbazóis/síntese química , Indazóis/síntese química , Receptor TIE-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Disponibilidade Biológica , Carbazóis/farmacocinética , Carbazóis/farmacologia , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor TIE-2/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Med Chem ; 55(3): 1082-105, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-22168626

RESUMO

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.


Assuntos
Isoxazóis/síntese química , Compostos de Fenilureia/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Quinazolinas/síntese química , Administração Oral , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Microssomos Hepáticos , Modelos Moleculares , Mutação , Transplante de Neoplasias , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo
11.
Mol Cancer Ther ; 11(4): 930-41, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22319199

RESUMO

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF(V600E) (K(d) BRAF(V600E) = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC(50) = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAF(V600E) versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10-55 mg/kg) of both pMEK and pERK in BRAF(V600E) colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30-100 mg/kg twice daily) against BRAF(V600E) melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development.


Assuntos
Antineoplásicos/farmacologia , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Quinazolinas/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Proliferação de Células , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas B-raf/genética , Quinazolinas/farmacocinética , Ratos , Ratos Sprague-Dawley
12.
Blood ; 111(5): 2765-75, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18057228

RESUMO

Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma , Pirazinas/farmacologia , Treonina/análogos & derivados , Administração Oral , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/química , Ácidos Borônicos/uso terapêutico , Bortezomib , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Camundongos Nus , Mieloma Múltiplo/patologia , NF-kappa B/antagonistas & inibidores , Neoplasias/patologia , Osteogênese/efeitos dos fármacos , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Ligante RANK/farmacologia , Treonina/administração & dosagem , Treonina/química , Treonina/farmacologia , Treonina/uso terapêutico , Resultado do Tratamento , Ubiquitina/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Curr Protoc Pharmacol ; Chapter 14: Unit 14.3, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21948162

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related deaths in the United States, with a 5-year survival rate of only 2% to 10%. This tumor is aggressive, often metastasizing to distant sites (liver, lung, and adjacent intestines) by the time of diagnosis. Treatment options are limited, and the disease carries a grave prognosis for most patients. An orthotopic model of human PDAC in nude mice provides an excellent way to evaluate the pathogenesis of tumor growth and metastasis in order to develop therapies, to better define the underlying biology of tumor growth and metastasis, and to identify new molecular targets. This unit describes an orthotopic model of human PDAC in athymic nude mice that closely mimics the human condition. It is characterized by diffuse peritoneal, lymphatic, and hepatic metastatic spread and manifestations of a cancer cachexic phenotype.


Assuntos
Adenocarcinoma/tratamento farmacológico , Caquexia/etiologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Transplante Heterólogo
14.
Curr Protoc Pharmacol ; Chapter 14: Unit 14.4, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21948163

RESUMO

Gastric carcinoma (GC) remains a leading cause of cancer related deaths worldwide with the 5-year survival rate in the U.S. at -5% to 15% with existing therapies. This tumor is aggressive and has often metastasized to distant sites (liver, lung, and adjacent intestine) by the time of diagnosis. Treatment options (surgery, radiation, and chemotherapy) are limited and the disease carries a grave prognosis for most patients (50% 5-year survival for distal GC; 10% 5-year survival for proximal GC). An orthotopic model of human GC in nude mice provides an excellent way to evaluate the pathogenesis of tumor growth and metastasis in order to develop effective therapies, as well as to better understand the underlying biology of gastric tumor growth and metastasis. The protocol described in this unit details the development and characterization of an orthotopic model of human GC in athymic nude mice with diffuse lymphatic and hepatic metastatic spread. This model closely mimics the course of the human disease.


Assuntos
Modelos Animais de Doenças , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas Experimentais/secundário , Metástase Linfática , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Gástricas/tratamento farmacológico , Transplante Heterólogo
15.
Curr Protoc Pharmacol ; Chapter 14: Unit 14.5, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21948164

RESUMO

Colorectal cancer is the second leading cause of cancer deaths in the United States with an estimated 150,000 diagnosed cases and over 56,000 fatalities annually (Jemal et al., 2006). Approximately one-third to one-half of cases are localized to the colon and rectum and have a favorable prognosis, while one-third to one-half present with regional lymph node metastases at diagnosis and generally are refractory to various chemotherapeutic regimens. Treatment options (surgery, radiation, and chemotherapy) are limited and the disease carries a grave prognosis for many patients. An orthotopic model of colon carcinoma in mice provides a way to evaluate the pathogenesis of tumor growth and metastasis as an aid in developing effective therapies and to better understand the underlying biology of colon tumor growth and metastasis. The protocol described in this unit details the development and characterization of an orthotopic model of murine colon carcinoma in BALB/c mice with diffuse lymphatic and hepatic metastatic spread, closely mimicking the course of the human disease.


Assuntos
Neoplasias do Colo/patologia , Modelos Animais de Doenças , Animais , Progressão da Doença , Feminino , Neoplasias Hepáticas Experimentais/secundário , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C
16.
Blood ; 99(11): 3885-91, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12010785

RESUMO

Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3- activating mutations.


Assuntos
Carbazóis/toxicidade , Inibidores Enzimáticos/farmacologia , Indóis , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/enzimologia , Células da Medula Óssea/patologia , Sobrevivência Celular/efeitos dos fármacos , Furanos , Humanos , Cinética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Mutação Puntual , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Células Tumorais Cultivadas , Tirosina Quinase 3 Semelhante a fms
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