Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Acta Diabetol ; 55(1): 49-57, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29064047

ABSTRACT

AIM: The zinc transporter 8 (ZnT8) has been suggested as a suitable target for non-invasive visualization of the functional pancreatic beta cell mass, due to both its pancreatic beta cell restricted expression and tight involvement in insulin secretion. METHODS: In order to examine the potential of ZnT8 as a surrogate target for beta cell mass, we performed mRNA transcription analysis in pancreatic compartments. A novel ZnT8 targeting antibody fragment Ab31 was radiolabeled with iodine-125, and evaluated by in vitro autoradiography in insulinoma and pancreas as well as by in vivo biodistribution. The evaluation was performed in a direct comparison with radio-iodinated Exendin-4. RESULTS: Transcription of the ZnT8 mRNA was higher in islets of Langerhans compared to exocrine tissue. Ab31 targeted ZnT8 in the cytosol and on the plasma membrane with 108 nM affinity. Ab31 was successfully radiolabeled with iodine-125 with high yield and > 95% purity. [125I]Ab31 binding to insulinoma and pancreas was higher than for [125I]Exendin-4, but could only by partially competed away by 200 nM Ab31 in excess. The in vivo uptake of [125I]Ab31 was higher than [125I]Exendin-4 in most tissues, mainly due to slower clearance from blood. CONCLUSIONS: We report a first-in-class ZnT8 imaging ligand for pancreatic imaging. Development with respect to ligand miniaturization and radionuclide selection is required for further progress. Transcription analysis indicates ZnT8 as a suitable target for visualization of the human endocrine pancreas.


Subject(s)
Diagnostic Imaging/methods , Immunoglobulin Fragments , Iodine Radioisotopes , Islets of Langerhans/diagnostic imaging , Peptides , Venoms , Zinc Transporter 8/immunology , Animals , Cells, Cultured , Exenatide , Immunoassay/methods , Immunoglobulin Fragments/metabolism , Insulin/metabolism , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Iodine Radioisotopes/analysis , Iodine Radioisotopes/metabolism , Islets of Langerhans/metabolism , Male , Mice , Molecular Diagnostic Techniques/methods , Pancreas/diagnostic imaging , Pancreas/metabolism , Peptides/analysis , Peptides/metabolism , Rats , Rats, Sprague-Dawley , Tissue Distribution , Venoms/analysis , Venoms/metabolism
2.
Br J Pharmacol ; 168(3): 673-85, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23004938

ABSTRACT

BACKGROUND AND PURPOSE: Drugs targeting microtubules are commonly used for cancer treatment. However, the potency of microtubule inhibitors used clinically is limited by the emergence of resistance. We thus designed a strategy to find new cell-permeable microtubule-targeting agents. EXPERIMENTAL APPROACH: Using a cell-based assay designed to probe for microtubule polymerization status, we screened a chemical library and identified two azaindole derivatives, CM01 and CM02, as cell-permeable microtubule-depolymerizing agents. The mechanism of the anti-tumour effects of these two compounds was further investigated both in vivo and in vitro. KEY RESULTS: CM01 and CM02 induced G2/M cell cycle arrest and exerted potent cytostatic effects on several cancer cell lines including multidrug-resistant (MDR) cell lines. In vitro experiments revealed that the azaindole derivatives inhibited tubulin polymerization and competed with colchicines for this effect, strongly indicating that tubulin is the cellular target of these azaindole derivatives. In vivo experiments, using a chicken chorioallantoic xenograft tumour assay, established that these compounds exert a potent anti-tumour effect. Furthermore, an assay probing the growth of vessels out of endothelial cell spheroids showed that CM01 and CM02 exert anti-angiogenic activities. CONCLUSIONS AND IMPLICATIONS: CM01 and CM02 are reversible microtubule-depolymerizing agents that exert potent cytostatic effects on human cancer cells of diverse origins, including MDR cells. They were also shown to inhibit angiogenesis and tumour growth in chorioallantoic breast cancer xenografts. Hence, these azaindole derivatives are attractive candidates for further preclinical investigations.


Subject(s)
Antineoplastic Agents/pharmacology , Indoles/pharmacology , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cells, Cultured , Chick Embryo , Chorioallantoic Membrane/pathology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Endothelial Cells/drug effects , Endothelial Cells/physiology , Humans , Indoles/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Tubulin Modulators/therapeutic use , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...