duramycin and Necrosis

Apoptosis (programmed cell death) and necrosis (uncontrolled cell death) are two distinct processes of cell death that have been described. Non-invasive molecular imaging of these two processes can have several clinical applications and has various approaches in pre-clinical research. Apoptosis imaging enables a specific and early measurement of response in cancer patients. In case of acute myocardial infarction (AMI) and cerebral stroke the degree of both apoptosis and necrosis is abundant. Imaging of both types of cell death is crucial for diagnosis and could differentiate between "real" and "rescuable" cell damage. In a pre-clinical setting cell death imaging offers the possibility for dynamic study protocols and repeated measurements of cell death in the same animal. This review provides an overview of the radiopharmaceutical development and in vivo evaluation of apoptosis and necrosis detecting radioligands that have emerged so far. Some apoptosis radiopharmaceuticals have made it to clinical trials ((99m)Tc-labeled Anx and (18)F-ML-10) while others need further optimization and evaluation (e.g., (18)F-WC-II-89). (99m)Tc-glucarate has been widely used in patients to image necrosis, but this radiopharmaceutical only works early after the onset of necrosis. Other necrosis avid probes like (123)I labeled hypericin and its monocarboxylic acid derivative and (99m)Tc(CO)(3)-bis-hydrazide-bis-DTPA pamoic acid need further evaluation but show already promising results for imaging of necrosis. As a general conclusion molecular imaging of both apoptosis and necrosis is necessary to understand the cell death process in several pathologies.

Topics: Animals; Annexin A5; Anthracenes; Antibodies, Monoclonal; Apoptosis; Bacteriocins; Cell Death; Glucaric Acid; Humans; Indoles; Models, Animal; Molecular Diagnostic Techniques; Molecular Probe Techniques; Myocardial Infarction; Necrosis; Organometallic Compounds; Organotechnetium Compounds; Peptides; Perylene; Radiopharmaceuticals; Stroke; Sulfonamides; Synaptotagmin I

Duramycin is a polypeptide that binds specifically to phosphatidylethanolamine (PE) on cell surfaces with high affinity, and has been shown to disrupt tumour cell surface-based coagulation and exhibit weak antimicrobial activity. The aim of the present study was to characterize the effect of duramycin on tumour cell proliferation and viability. Duramycin was used to detect phosphatidylethanolamine expression on cell lines by flow cytometry. Cells were cultured in the presence of duramycin and proliferation and cell viability assessed. Electron microscopy and confocal microscopy were utilized to investigate cell membrane structure after duramycin treatment. Pancreatic tumour cells were shown to express phosphatidylethanolamine on their cell surfaces by specific labelling with duramycin. Phosphatidylethanolamine expression was generally increased in apoptotic cells and more so in necrotic cells. Cells cultured in the presence of duramycin showed increasing levels of apoptosis and ultimately necrosis with increasing duramycin concentrations, and cell proliferation was reduced in a duramycin dose-dependent manner between 0.125 and 12.5 μmol/l. Tissue factor expression was also reduced when cells were cultured in the presence of duramycin. Cells imaged by electron microscopy were fragile, suggesting that membrane integrity was compromised by duramycin, although no obvious differences in membrane structure were observed by live cell confocal imaging. Duramycin induced apoptosis and exhibited antiproliferative and anticoagulant effects on pancreatic tumour cells, most probably by disrupting cell membrane structure and/or function.

Topics: Antineoplastic Agents; Apoptosis; Bacteriocins; Cell Adhesion; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Microscopy, Confocal; Microscopy, Electron; Necrosis; Peptides; Phosphatidylethanolamines; Thromboplastin