RESUMO
Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.
Assuntos
Antituberculosos/farmacocinética , Compostos Aza/farmacocinética , Glucanos/química , Glucanos/farmacocinética , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/farmacocinética , Animais , Antituberculosos/química , Área Sob a Curva , Compostos Aza/sangue , Compostos Aza/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Colônia Microbiana , Compostos de Dansil/química , Relação Dose-Resposta a Droga , Fluoroquinolonas , Glucanos/sangue , Meia-Vida , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moxifloxacina , Quinolinas/sangue , Quinolinas/químicaAssuntos
Mycobacterium tuberculosis/genética , Alelos , Sequência de Bases , Feminino , Humanos , Repetições Minissatélites , Dados de Sequência Molecular , Filogenia , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Sibéria , Especificidade da Espécie , Tuberculose Pulmonar/microbiologiaRESUMO
The growth of Krebs-2 carcinoma in BCG-prevaccinated virgin female C57BL/6, CC57BR/M, and C3Hf mice was studied in relation to the number of living mycobacteria in the organism. When the number of mycobacteria was high, tumor growth was stimulated. After the bacteria were eliminated, tumor growth was inhibited. The effect of BCG was based, on the one hand, on the diversion of effector cells, presumably macrophages, responsible for tumor defense and, on the other hand, on the activation of the pool of these cells. The conclusions were reached that high doses of BCG may be dangerous in human cancer immunotherapy and that patients predisposed to neoplastic disease should be revaccinated with BCG.
Assuntos
Vacina BCG/administração & dosagem , Carcinoma Krebs 2/terapia , Animais , Carcinoma Krebs 2/imunologia , Carcinoma Krebs 2/microbiologia , Relação Dose-Resposta Imunológica , Feminino , Imunidade , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium bovis/isolamento & purificaçãoRESUMO
The effect of BCG vaccine on the growth of imtransplants of Krebs-2 carcinoma in mice was studied. The simultaneous injection of BCG and tumor cells either inhibited tumor growth (BCG given in admixture with tumor cells) or stimulated it (BCG injected contralateral to the tumor transplantation site). The BCG dose was directly related to the effect. Tumor growth was also stimulated by the ip injection of starch or liquid paraffin. In these experiments, the BCG effect was attributed to the redistribution of cells involved in nonspecific and specific tumor resistance. Shortly after BCG prevaccination, particularly when BCG doses were high and mice were susceptible to vaccine infection, BCG was either without effect or stimulated tumor growth; later, however, tumor growth was inhibited regardless of the BCG dose and the injection site of the BCG. The effect of BCG prevaccination was suggested to be due to: 1)the distraction of macrophages and T-lymphocytes to defend the host against the multiplying mycobacteria, and 2)the activation of the pool of these cells that become capable to participate in antitumor resistance after mycobacteria elimination.