APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo

Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted

Разработка и применение современных лабораторных методов в эпидемиологическом мониторинге, диагностики и лечении энтеровирусных инфекций

У роботі проведена порівняльна оцінка специфічності й чутливості тест-системи ПЛР, зі специфічним праймером до ДНК 207 п.н. 5'-нетрансльованої області генома энтеровируса для всіх типів ентеровірусів (крім вірусу поліомієліту) у порівнянні із класичним культуральним методом. А також методологічний підхід спільного використання вищеописаної реакції ПЦР із визначенням антитіл класу Іg до вірусів Коксаки й ЕСНО у системі ІФА діагностики, розробленої авторами, і спектр застосування розробленого комплекс.In work the estimation of specificity and sensitivity of test system PTSR, with specific primers to DNA 207 n.n is spent comparative. 5 '-not broadcast areas генома an enterovirus for all types of enteroviruses (except a poliomyelitis virus) in comparison with classical the virology a method. And also the methodological approach of sharing of above described reaction PCR with definition of antibodies of a class ІgG to viruses Cocsaki and ЕСНО in system IFA of diagnostics developed by authors, and a spectrum of application of the developed complex

Glioma tropism of lentivirally transduced hematopoietic progenitor cells

Experimental gliomas attract hematopoietic progenitor cells (HPC) in vivo. HPC are therefore promising candidates for a cell-based delivery of therapeutic molecules to experimental gliomas. A therapeutic application requires efficient genetic manipulation of the cellular vector and a lack of tumorigenicity. Here, we studied the impact of lenti-viral transduction on the glioma tropism of human or murine HPC. Transduction of human or murine HPC with a GFP lentivirus (lenti-GFP) did not interfere with the glioma-mediated attraction of HPC. Bone marrow reconstitution of C57Bl/6 mice with syngeneic GFP-transgenic lineage-depleted bone marrow cells (lin- BM) was as efficient as reconstitution with syngeneic lin- BM transduced ex vivo with lenti-GFP. SMA-560 gliomas growing orthotopically in lenti-GFP-reconstituted VM/Dk mice recruited GFP-positive bone marrow-derived cells. Thus, lentiviral transduction did not interfere with the attraction of exogenously injected HPC or endogenous bone marrow-derived cells by experimental gliomas. Lenti-GFP-HPC implanted directly into tumor-free brains were not tumorigenic. The intravenous injection of lenti-GFP-HPC in glioma-bearing mice did not alter the survival of otherwise untreated animals and had no impact on the survival benefit conferred by cerebral irradiation. Taken together, genetic manipulation of HPC with lenti-GFP neither made these cells tumorigenic nor interfered with their glioma tropism

Monitoring the glioma tropism of bone marrow-derived progenitor cells by 2-photon laser scanning microscopy and positron emission tomography

Intracerebral experimental gliomas attract intravenously injected murine or human bone marrow-derived hematopoietic progenitor and stem cells (HPC) in vitro, ex vivo, and in vivo, indicating that these progenitor cells might be suitable vehicles for a cell-based delivery of therapeutic molecules to malignant gliomas. With regard to therapeutic application, it is important to investigate cell fates in vivo (i.e., the time-dependent intratumoral and systemic distribution after intravenously injection). Conventional histological analysis has limitations in this regard because longitudinal monitoring is precluded. Here, we used 2-photon laser scanning microscopy (2PLSM), positron emission tomography (PET), and MRI to study the fate of intravenously injected HPC carrying fluorescence, bioluminescence, and PET reporter genes in glioma-bearing mice. Our 2PLSM-based monitoring studies revealed that HPC homing to intracerebral experimental gliomas occurred already within the first 6 h and was most efficient within the first 24 h after intravenous injection. The highest PET signals were detected in intracerebral gliomas, whereas the tracer uptake in other organs, notably spleen, lung, liver, and muscle, remained at background levels. The results have important implications for designing schedules for therapeutic cell-based anti-glioma approaches. Moreover, the PET reporter-based imaging technique will allow noninvasive monitoring of cell fate in future cell-based therapeutic antiglioma approaches

APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo

Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted