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1.
J Microencapsul ; 29(6): 539-48, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22375686

RESUMO

The aim of the present study is to develop microemulsion and liposome carrier systems for oral administration of transforming growth factor alpha (TGF-α) and to investigate the effects of these carrier systems on the gastrointestinal efficiency in rats. Microemulsion (w/o) and liposomes (MLV) were developed and characterised. The carrier systems were administered intragastrically by gastric cannula to male Wistar rats. The highest reduction in the basal acid secretion was observed in the microemulsion containing TGF-α and aprotinin group (TAME).The gastric mucus secretion in microemulsion containing TGF-α (TME) and TAME treatment groups increased significantly compared to the other groups. TGF-α levels in both stomach and duodenum were significantly increased in the TAME group. As a result, it was determined through confocal laser scanning microscope (CLSM) studies that exogenous-applied TGF-α attached to endogenous EGF receptors. The microemulsion formulation was found to be a more suitable carrier system for oral administration of TGF-α.


Assuntos
Receptores ErbB/metabolismo , Mucinas Gástricas/metabolismo , Mucosa Gástrica/metabolismo , Fator de Crescimento Transformador alfa , Animais , Aprotinina/química , Aprotinina/farmacocinética , Aprotinina/farmacologia , Emulsões , Lipossomos , Masculino , Ratos , Ratos Wistar , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Fator de Crescimento Transformador alfa/química , Fator de Crescimento Transformador alfa/farmacocinética , Fator de Crescimento Transformador alfa/farmacologia
2.
Technol Cancer Res Treat ; 5(3): 201-13, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16700617

RESUMO

Despite advances in our knowledge about the genesis, molecular biology, and natural history of malignant gliomas and the use of a multi-disciplinary approach to their treatment, patients harboring this diagnosis continue to face a grim prognosis. At the time of diagnosis, patients typically undergo surgery for the establishment of a histologic diagnosis, the reduction of tumor burden, and the relief of mass effect, with the maintenance of the patient's neurological function in mind. This is followed by the administration of adjuvant therapeutics, including radiation therapy and chemotherapy. Many investigational agents with laboratory evidence of efficacy against malignant gliomas have not met their promise in the clinical setting, largely due to the barriers that they must overcome to reach the tumor at a therapeutically meaningful concentration for a durable period of time. The relevant aspects of the blood-brain barrier, blood-tumor barrier, and blood-cerebrospinal fluid barrier, as they pertain to the delivery of agents to the tumor, will be discussed along with the strategies devised to circumvent them. This discussion will be followed by a description of agents currently in preclinical and clinical development, many of which are the result of intense ongoing research into the molecular biology of gliomas.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Convecção , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/farmacocinética , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Toxina Diftérica/administração & dosagem , Toxina Diftérica/farmacocinética , Exotoxinas/administração & dosagem , Exotoxinas/farmacocinética , Glioma/metabolismo , Humanos , Interleucina-13/administração & dosagem , Interleucina-13/farmacocinética , Interleucina-4/administração & dosagem , Interleucina-4/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética , Transferrina/administração & dosagem , Transferrina/análogos & derivados , Transferrina/farmacocinética , Fator de Crescimento Transformador alfa/administração & dosagem , Fator de Crescimento Transformador alfa/farmacocinética
3.
Scand J Clin Lab Invest ; 59(3): 191-7, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10400163

RESUMO

Studies on the relative potency of ligands for the epidermal growth factor receptor are usually performed with highly purified ligand specimens. However, adsorption of ligands to glass and plastic surfaces may affect the results by reducing the ligand concentration in an unpredictable way. The aim of this study was to examine the adsorption of four epidermal growth factor (EGF) receptor ligands, EGF, transforming growth factor alpha (TGF-alpha), heparin binding-EGF (HB-EGF) and betacellulin, to commonly used test tubes of polyethylene, polystyrene and glass, respectively. The ligands were kept in a sodium phosphate buffer, both with and without 0.1% human albumin as carrier protein. Adsorption was examined after 20 minutes at room temperature as well as after overnight storage at 4 degrees C. The ligands were quantitated by ELISAs. In the buffer not containing 0.1% human albumin there was a marked adsorption, which differed both among the ligands and among the test tubes. After 20 minutes the ligand concentrations were reduced to 33-73% in polyethylene tubes, to 15-46% in polystyrene tubes and to 12-29% in glass tubes. The adsorption was even more pronounced after storage overnight. The use of 0.1% human albumin in the buffer solved the problem in polyethylene and polystyrene tubes, but not in glass tubes. The results demonstrate that adsorption to surfaces can be a significant problem for EGF receptor ligands and emphasize the need for controlling the growth factor concentration in the final experimental setting.


Assuntos
Fator de Crescimento Epidérmico/farmacocinética , Receptores ErbB/metabolismo , Vidro , Peptídeos e Proteínas de Sinalização Intercelular , Polietilenos , Adsorção , Betacelulina , Química Clínica/normas , Ensaio de Imunoadsorção Enzimática/normas , Fator de Crescimento Epidérmico/análise , Fator de Crescimento Epidérmico/farmacologia , Substâncias de Crescimento/análise , Substâncias de Crescimento/farmacocinética , Substâncias de Crescimento/farmacologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Ligantes , Poliestirenos , Ligação Proteica , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Reprodutibilidade dos Testes , Fator de Crescimento Transformador alfa/análise , Fator de Crescimento Transformador alfa/farmacocinética , Fator de Crescimento Transformador alfa/farmacologia
4.
Muscle Nerve ; 20(7): 815-22, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9179153

RESUMO

Although a number of cytokines have been implicated in tissue regeneration, it is unknown which ones actually function in vivo. Here, we use mice with a targeted mutation in the leukemia inhibitory factor (LIF) gene to examine the role of LIF in muscle regeneration. Using a muscle crush model, we show that muscle regeneration in LIF knockout mice is significantly, reduced compared to control littermates. Further, targeted infusion of LIF in both normal and LIF knockout animals stimulated muscle regeneration, but the stimulation observed was much greater in the mutant animals than in controls. In contrast, interleukin-6 and transforming growth factor-alpha, which also stimulate myoblast proliferation in vitro, had no effect on regeneration. These findings demonstrate directly that LIF is involved in regeneration of injured muscle and points to the use of LIF as a therapeutic agent in the treatment of neuromuscular disease.


Assuntos
Inibidores do Crescimento/farmacocinética , Linfocinas/farmacocinética , Músculo Esquelético/fisiologia , Regeneração/efeitos dos fármacos , Animais , Divisão Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Inibidores do Crescimento/genética , Interleucina-6/farmacocinética , Radioisótopos do Iodo , Fator Inibidor de Leucemia , Linfocinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/lesões , Proteínas Recombinantes/farmacologia , Regeneração/genética , Fator de Crescimento Transformador alfa/farmacocinética
5.
Eur J Nucl Med ; 23(4): 448-52, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8612667

RESUMO

The Watson-Crick base pairing rule provides the underlying principle for the antisense (AS) approach to inhibiting gene expression. Transforming growth factor alpha (TGFalpha) was the first growth factor to be associated with tumorigenesis, thus making the TGFalpha (mRNA) a potential target for AS therapy and offering the potential for monitoring of the progression of malignancy by non-invasive imaging with radiolabelled AS phosphodiester. Probe labelling and biodistribution were studied in the present report. A 23-mer oligonucleotide sequence was synthesized and grafted in 5' with a tyramine group which was further radioiodinated. The radiolabelled AS was injected intratumorally in mammary tumour-bearing BALB/c mice (3 weeks after inoculation of 7.10(6)NS2T2A mammary cells). Biodistribution was monitored by sequential scintigraphy and organ radioactivity after autopsy. The 5' tyramine group allowed specific and stable radiolabelling of the AS with 125I. The 125I AS oligonucleotide was rapidly cleared from the tumour by intestine and kidneys. Four hours after intratumoral injection, 6.5%+/-1.5% of the dose was retained in the tumour as non-degraded 125I AS. It is concluded that 5' tyraminylated AS provides information on the biodistribution of AS oligonucleotide following intratumoral injection. These data will contribute to the pharmacology of AS oligonucleotides which can be used for therapy.


Assuntos
Radioisótopos do Iodo/farmacocinética , Oligonucleotídeos Antissenso , Fator de Crescimento Transformador alfa/farmacocinética , Transplante Heterólogo , Abdome/diagnóstico por imagem , Animais , Estabilidade de Medicamentos , Feminino , Humanos , Neoplasias Mamárias Experimentais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Transplante de Neoplasias , Cintilografia , Glândula Tireoide/diagnóstico por imagem , Fatores de Tempo , Distribuição Tecidual , Células Tumorais Cultivadas/transplante
6.
Cancer Res ; 53(19): 4588-94, 1993 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8402632

RESUMO

Modification of proteins with monomethoxy-polyethylene glycol (mPEG) has been shown to prolong circulation time and to reduce immunogenicity. To make a mPEG-modified recombinant toxin that retained cytotoxic activity but had a longer residence time in circulation, we have constructed an altered form of TGF alpha-PE40, a recombinant toxin composed of human transforming growth factor alpha (TGF alpha) fused to a fragment of Pseudomonas exotoxin (PE38) devoid of its cell-binding domain. In the newly designed protein, termed TGF alpha R29-L2-CH2-PE38QQ delta (TCP), there are no lysine residues in the TGF alpha and PE38 portions. Human IgG4 constant region CH2 and a tetradecapeptide linker; L2, are inserted between TGF alpha and PE38. Together, L2 and CH2 contain 13 lysine residues as potential modification sites for mPEG. mPEG conjugates of TCP (PEG-TCP) were generated and the products were resolved by ion exchange chromatography. Two PEG-TCP species termed B4 and B6 retained 15 and 4% of cytotoxicity, respectively, and 26% of their receptor binding activity compared with the unmodified TCP. Both B4 and B6 had prolonged circulation times in the blood and reduced toxicity in animals. The mean residence times of B4 and B6 were 37 and 68 min, respectively, compared to 7 min for TCP. When administered i.v. to tumor bearing mice, both B4 and B6 produced marked antitumor effects whereas the unmodified TCP had none. Also, the immunogenicity of PEG-TCP was 5-10 times less than that of TCP. We suggest that the prolonged circulating time and reduced toxicity of PEG-TCP compensate for a diminished cytotoxic activity and enlarge significantly the therapeutic window of this chimeric toxin.


Assuntos
ADP Ribose Transferases , Toxinas Bacterianas , Carcinoma de Células Escamosas/tratamento farmacológico , Exotoxinas/uso terapêutico , Imunotoxinas/uso terapêutico , Polietilenoglicóis , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador alfa/uso terapêutico , Fatores de Virulência , Sequência de Aminoácidos , Animais , Anticorpos/análise , Clonagem Molecular , Escherichia coli , Exotoxinas/farmacocinética , Humanos , Regiões Constantes de Imunoglobulina , Imunoglobulina G/classificação , Imunotoxinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico , Pseudomonas aeruginosa , Proteínas Recombinantes de Fusão/farmacocinética , Fator de Crescimento Transformador alfa/farmacocinética , Transplante Heterólogo , Células Tumorais Cultivadas , Exotoxina A de Pseudomonas aeruginosa
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