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1.
Clin Cancer Res ; 14(7): 2145-53, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18381956

RESUMO

PURPOSE: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel peptidic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan. EXPERIMENTAL DESIGN: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker. The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species. RESULTS: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro. Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronide metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents. CONCLUSIONS: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Portadores de Fármacos , Neoplasias Experimentais/tratamento farmacológico , Peptídeos/química , Peptídeos/síntese química , Peptídeos/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Camptotecina/síntese química , Camptotecina/química , Camptotecina/metabolismo , Camptotecina/farmacologia , Cátions , Cães , Humanos , Irinotecano , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Neuron ; 39(4): 613-24, 2003 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-12925276

RESUMO

Prostaglandin E(2) (PGE(2)) and epinephrine act directly on nociceptors to produce mechanical hyperalgesia through protein kinase A (PKA) alone or through a combination of PKA, protein kinase C epsilon (PKCepsilon), and extracellular signal-regulated kinase (ERK), respectively. Disruptors of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) markedly attenuated the hyperalgesia in rat paws caused by injection of epinephrine or its downstream mediators. In contrast, the hyperalgesia induced by PGE(2) or its mediators was not affected by any of the cytoskeletal disruptors. These effects were mimicked in vitro, as measured by enhancement of the tetrodotoxin-resistant sodium current. When PGE(2) hyperalgesia was shifted to dependence on PKCepsilon and ERK as well as PKA, as when the tissue is "primed" by prior treatment with carrageenan, it too became dependent on an intact cytoskeleton. Thus, inflammatory mediator-induced mechanical hyperalgesia was differentially dependent on the cytoskeleton such that cytoskeletal dependence correlated with mediation by PKCepsilon and ERK.


Assuntos
Citoesqueleto/fisiologia , Neurônios Aferentes/fisiologia , Dor/fisiopatologia , Sistemas do Segundo Mensageiro/fisiologia , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico , Dinoprostona/metabolismo , Eletrofisiologia , Epinefrina/metabolismo , Hiperalgesia/induzido quimicamente , Imuno-Histoquímica , Inflamação/fisiopatologia , MAP Quinase Quinase Quinase 3 , MAP Quinase Quinase Quinases/metabolismo , Masculino , Microscopia Confocal , Nociceptores/fisiologia , Técnicas de Patch-Clamp , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Quimiocinas/fisiologia
3.
J Neuroimmunol ; 186(1-2): 54-62, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17442405

RESUMO

In wild-type FVB mice, leukocyte recruitment to lipopolysaccharide was sexually dimorphic, with a greater number of leukocytes recruited in females. In male beta(2)-adrenergic receptor knock out mice (bred on a congenic FVB background) the number of leukocytes recruited was increased approximately 4-fold, while in females there was no change, eliminating sexual dimorphism in leukocyte migration. While there were significantly fewer recruited CD62L(+) and CD11a(+) leukocytes in wild-type males, only in male beta-adrenergic receptor knock out mice was there an increase in the number of recruited CD11a(+) leukocytes, again eliminating sexual dimorphism. Thus, leukocyte migration and CD11a(+) adhesion molecule expression in male, but not in female, leukocytes is beta-adrenergic receptor-dependent. Our findings provide support for a role of beta(2)-adrenergic receptor mechanisms in the inflammatory response, and suggest that beta(2)-adrenergic receptor on male leukocytes contributes to sexual dimorphism in the effect of stress on inflammatory diseases.


Assuntos
Movimento Celular/fisiologia , Leucócitos/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Caracteres Sexuais , Análise de Variância , Animais , Antígeno CD11a/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular/efeitos dos fármacos , Feminino , Selectina L/metabolismo , Leucócitos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Receptores Adrenérgicos beta 2/deficiência
4.
Biochem J ; 390(Pt 2): 407-18, 2005 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15859953

RESUMO

Short peptide sequences that are able to transport molecules across the cell membrane have been developed as tools for intracellular delivery of therapeutic molecules. This work describes a novel family of cell-penetrating peptides named Vectocell peptides [also termed DPVs (Diatos peptide vectors)]. These peptides, originating from human heparin binding proteins and/or anti-DNA antibodies, once conjugated to a therapeutic molecule, can deliver the molecule to either the cytoplasm or the nucleus of mammalian cells. Vectocell peptides can drive intracellular delivery of molecules of varying molecular mass, including full-length active immunoglobulins, with efficiency often greater than that of the well-characterized cell-penetrating peptide Tat. The internalization of Vectocell peptides has been demonstrated to occur in both adherent and suspension cell lines as well as in primary cells through an energy-dependent endocytosis process, involving cell-membrane lipid rafts. This endocytosis occurs after binding of the cell-penetrating peptides to extracellular heparan sulphate proteoglycans, except for one particular peptide (DPV1047) that partially originates from an anti-DNA antibody and is internalized in a caveolar independent manner. These new therapeutic tools are currently being developed for intracellular delivery of a number of active molecules and their potentiality for in vivo transduction investigated.


Assuntos
Membrana Celular/metabolismo , Portadores de Fármacos/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação Microbiológicos/genética , Linhagem Celular , Núcleo Celular/química , Núcleo Celular/metabolismo , Citosol/química , Citosol/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Portadores de Fármacos/toxicidade , Humanos , Integrases/metabolismo , Cinética , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/toxicidade , Transporte Proteico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Recombinação Genética/genética , Temperatura , Proteínas Virais/metabolismo
5.
Br J Pharmacol ; 140(1): 133-45, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12967943

RESUMO

(1) L-selectin, constitutively expressed by leukocytes, is involved in the initial binding of leukocytes to activated endothelium. Anti-inflammatory drugs like glucocorticoids can induce shedding of L-selectin, but the mechanism is still unknown. Annexin 1, a protein whose synthesis and externalization/secretion are induced during the inflammatory response, has been proposed as a mediator of the anti-inflammatory actions of glucocorticoids. (2) The monocytic cell line U-937 strongly expresses Annexin 1 after 24 h of phorbol 12-myristate 13-acetate (PMA, 1 nm) treatment and externalizes/releases the protein after additional 16 h of dexamethasone (1 microm) treatment. (3) This study investigated the possible regulation of cell surface L-selectin shedding by endogenous Annexin 1, and its role in glucocorticoid-induced L-selectin shedding in the U-937 cell line. (4) PMA- and dexamethasone treatment-induced L-selectin shedding was potentially mediated by Annexin 1, since neutralizing antibodies against Annexin 1 reduced dexamethasone- and Annexin 1-induced shedding. (5) Immunoprecipitation and binding assays provided support for the suggestion that this effect could be mediated by an interaction between externalized Annexin 1 and L-selectin. Such interaction involved the N-terminal domain of Annexin 1 and was calcium-dependent. Confocal microscopy studies demonstrated increased colocalization of Annexin 1 and L-selectin on the cell surface. (6) Overall, our study provides new insights into the potential role of endogenous ANXA1 as a mediator of dexamethasone-induced L-selectin shedding, which may contribute to the anti-inflammatory activity of glucocorticoids.


Assuntos
Anexina A1/metabolismo , Dexametasona/farmacologia , Selectina L/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Células U937
6.
Br J Pharmacol ; 143(8): 1033-41, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15477226

RESUMO

While the mechanisms underlying the marked sexual dimorphism in inflammatory diseases are not well understood, the sexually dimorphic sympathoadrenal axis profoundly affects the inflammatory response. We tested whether adrenergic receptor-mediated activation of human neutrophil function is sexually dimorphic, since neutrophils provide the first line of defense in the inflammatory response. There was a marked sexual dimorphism in beta(2)-adrenergic receptor binding, using the specific beta(2)-adrenergic receptor ligand, [(3)H]-dihydroalprenolol, with almost three times more binding sites on neutrophils from females (20,878 +/- 2470) compared to males (7331 +/- 3179). There was also a marked sexual dimorphism in the effects of isoprenaline, a beta-adrenergic receptor agonist, which increased nondirected locomotion (chemokinesis) in neutrophils obtained from females, while having no effect on neutrophils from males. Isoprenaline stimulated the release of a chemotactic factor from neutrophils obtained from females, but not from males. This chemotactic factor acts on the G protein-coupled CXC chemokine receptor 2 (CXCR2) chemokine receptor, since an anti-CXCR2 antibody and the selective nonpeptide CXCR2 antagonist SB225002, inhibited chemotaxis produced by this factor. While interleukin- (IL-) 8 is a principal CXCR2 ligand, isoprenaline did not produce an increase in IL-8 release from neutrophils. IL-8-induced chemotaxis was inhibited in a sexually dimorphic manner by isoprenaline, which also stimulated release of a mediator from neutrophils that induced chemotaxis, that was inhibited by anti-CXCR2 antibodies. These findings indicate an important role for adrenergic receptors in the modulation of neutrophil trafficking, which could contribute to sex-differences in the inflammatory response.


Assuntos
Neutrófilos/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Caracteres Sexuais , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Isoproterenol/farmacologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos
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