Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Sci Transl Med ; 8(325): 325ra17, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26865565

RESUMO

Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.


Assuntos
Aurora Quinases/antagonistas & inibidores , Nanopartículas/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Aurora Quinases/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Masculino , Espectrometria de Massas , Camundongos , Camundongos SCID , Organofosfatos/química , Organofosfatos/farmacocinética , Organofosfatos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos Nus , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Mol Cancer Ther ; 5(12): 3052-61, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17172407

RESUMO

Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Lactonas/farmacologia , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Pirazinas/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/química , Ligação Competitiva , Ácidos Borônicos/química , Bortezomib , Estabilidade de Medicamentos , Feminino , Células HT29 , Células HeLa , Humanos , Lactonas/química , Camundongos , Camundongos Nus , Camundongos SCID , Inibidores de Proteases/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/química , Pirróis/química , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Invest Dermatol ; 123(6): 1176-81, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15610531

RESUMO

The fibronectins (FN) comprise a family of adhesive extracellular matrix proteins thought to mediate important functions in cutaneous wounds. Plasma fibronectin (pFN) extravasates for days from intact hyperpermeable vessels following injury whereas mRNAs encoding the cellular fibronectins (cFN) that include two segments, termed EIIIA (EDA) and EIIIB (EDB), are expressed by wound cells. Wounds in mice null for pFN appear to heal normally whereas those in EIIIA null mice exhibit defects, suggesting that cFN may play a role when pFN is missing. Integrin alpha9beta1, a receptor for several extracellular matrix proteins as well as the EIIIA segment, is expressed normally in the basal layer of squamous epithelia. We report results from immunohistochemistry on healing wounds demonstrating that EIIIA-containing cFN are deposited abundantly but transiently from day 4 to 7 whereas EIIIB-containing cFN persist at least through day 14. Elevated expression of alpha9beta1 is seen in basal and suprabasal epidermal keratinocytes in wounds. The spatial expression patterns of cFN and alpha9beta1 are distinct, but overlap in the dermal-epidermal junction, and both are expressed contemporaneously. These observations suggest a role for alpha9beta1-EIIIA interactions in wound keratinocyte function.


Assuntos
Derme/metabolismo , Epiderme/metabolismo , Fibronectinas/metabolismo , Integrinas/metabolismo , Cicatrização/fisiologia , Animais , Arteríolas/metabolismo , Movimento Celular/fisiologia , Derme/citologia , Células Epidérmicas , Feminino , Imuno-Histoquímica , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/metabolismo , Ratos , Ratos Endogâmicos
5.
Blood ; 104(12): 3754-7, 2004 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-15304388

RESUMO

Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.


Assuntos
Mutação de Sentido Incorreto , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mastocitose Sistêmica/tratamento farmacológico , Mastocitose Sistêmica/genética , Camundongos , Piperazinas/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia
6.
Cancer Res ; 62(3): 789-95, 2002 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11830534

RESUMO

Antiangiogenic therapy, although effective in shrinking tumors, has not yet been established as a standalone treatment for cancer. This therapeutic limitation can be overcome by combining angiogenesis inhibitors with chemotherapeutic agents. NM-3, a small molecule isocoumarin, is a recently discovered angiogenesis inhibitor. Here we demonstrate that NM-3 inhibits the proliferation of human umbilical vein endothelial cells in vitro, at concentrations 10-fold less than those required to inhibit normal fibroblasts or tumor cells (HT29, MKN28, and MCF-7). NM-3 alone inhibits endothelial sprouting and tube formation in vitro. The results also show that synergistic antiproliferative activity is observed when human umbilical vein endothelial cells are treated with NM-3 in combination with 5-fluorouracil. The effects of treatment with NM-3 and various chemotherapeutic agents were also evaluated in tumor xenografts. The results demonstrate that combined treatment with NM-3 and chemotherapeutic agents significantly reduced mean tumor volume compared with either treatment alone, with no effects on body weight changes. Taken together, these findings demonstrate that NM-3 is a well-tolerated angiogenesis inhibitor that significantly increases the efficacy of existing antineoplastic agents.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/crescimento & desenvolvimento , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Ciclofosfamida/farmacologia , Sinergismo Farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Inibidores do Crescimento/farmacologia , Humanos , Isocumarinas , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Morphol ; 203(3): 361-375, 1990 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29865715

RESUMO

Six different lectins were used to study the carbohydrate nature of the hyaline layer (HL), the external extracellular matrix of the starfish embryo. Thin sections of embryos fixed in the late gastrula stage were incubated with five fluoresceinated lectins: Con A, WGA, RCA, UEA-I, and SBA. All but UEA-I labelled the HL, suggesting that the following sugars are present: mannose and/or glucose, glcNAc and/or Neu5Ac, galactose, and galNAc. The different lectins produced variable degrees of labelling, with WGA, RCA, and SBA producing more intense labelling than Con A. Binding of lectins by the HL was studied at the ultrastructural level by exposing ultrathin sections to the following lectin-gold conjugates: Con A, WGA, PNA, SBA, and LFA. Lectin binding was observed over the various regions of the HL, recognized by Crawford and Abed (J. Morphol. 176:235-246, '86), i.e., the intervillus layer, the supporting layer and the coarse outer meshwork. Local differences in labelling patterns were observed among the various lectins, with SBA labelling all regions intensely, WGA and PNA labelling the supporting layer predominantly, and Con A labelling the HL only lightly. No labelling was observed with LFA. These lectin-labelling patterns in the HL demonstrate the presence of different glycoconjugates in different regions of the HL, suggesting that the layers differ biochemically. The existence of biochemical differences strengthens the idea that each layer may have different functions in the developing starfish embryo.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...