The Experts below are selected from a list of 858 Experts worldwide ranked by ideXlab platform
Hansjörg Eibl - One of the best experts on this subject based on the ideXlab platform.
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Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins
Journal of cancer research and clinical oncology, 2012Co-Authors: Ilina K. Dineva, Hansjörg Eibl, Maya M. Zaharieva, Spiro Konstantinov, Martin R. BergerAbstract:Purpose This study investigated the antineoplastic effect of the membrane active Alkylphosphocholine erufosine in breast carcinoma models in vitro and in vivo and determined its influence on the PI3K/Akt and Ras/Raf/MAPK signaling pathways.
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Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy
Radiation oncology (London England), 2009Co-Authors: Guido Henke, Hansjörg Eibl, Lars H. Lindner, Michael Vogeser, Jürgen Wörner, Arndt Christian Müller, Michael Bamberg, Kirsten Wachholz, Claus Belka, Verena JendrossekAbstract:Background Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable Alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.
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Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy
Radiation Oncology, 2009Co-Authors: Guido Henke, Hansjörg Eibl, Lars H. Lindner, Michael Vogeser, Jürgen Wörner, Arndt Christian Müller, Michael Bamberg, Kirsten Wachholz, Claus Belka, Verena JendrossekAbstract:Background Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable Alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice. Methods NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity. Results Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (
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The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro
Radiation Oncology, 2006Co-Authors: Amelie Rübel, Hansjörg Eibl, Lars H. Lindner, Claus Belka, René Handrick, Matthias Steiger, Wilfried Budach, Verena JendrossekAbstract:Background Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable Alkylphosphocholine erucylphosphocholine (ErPC) is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro. ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine™ on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro.
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The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro
Radiation Oncology, 2006Co-Authors: Amelie Rübel, Hansjörg Eibl, Lars H. Lindner, Claus Belka, René Handrick, Matthias Steiger, Wilfried Budach, Verena JendrossekAbstract:Background Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable Alkylphosphocholine erucylphosphocholine (ErPC) is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro . ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine™ on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro . Results While all cell lines showed high intrinsic resistance against radiation-induced apoptosis as determined by fluorescence microscopy, treatment with ErPC and ErPC3 strongly increased sensitivity of the cells to radiation-induced cell death (apoptosis and necrosis). T98G cells were most responsive to the combined treatment revealing highly synergistic effects while A172 showed mostly additive to synergistic effects, and U87MG cells sub-additive, additive or synergistic effects, depending on the respective radiation-dose, drug-concentration and treatment time. Combined treatment enhanced therapy-induced damage of the mitochondria and caspase-activation. Importantly, combined treatment also increased radiation-induced eradication of clonogenic T98G cells as determined by standard colony formation assays. Conclusion Our observations make the combined treatment with ionizing radiation and the membrane targeted apoptosis modulators ErPC and ErPC3 a promising approach for the treatment of patients suffering from malignant glioma. The use of this innovative treatment concept in an in vivo xenograft setting is under current investigation.
John S. Kuo - One of the best experts on this subject based on the ideXlab platform.
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Diapeutic cancer-targeting Alkylphosphocholine analogs may advance management of brain malignancies.
CNS oncology, 2016Co-Authors: Ray R. Zhang, Kyle I. Swanson, Lance T. Hall, Jamey P. Weichert, John S. KuoAbstract:The following is a special report on Alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment in glioblastoma and brain metastases. These novel cancer-targeting agents display impressive tumor avidity with low background in the normal brain, and multimodal diagnostic imaging and therapy capabilities. The use of these agents may significantly improve diagnosis, treatment and post-treatment follow-up in patients with brain malignancies
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Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood–Brain Barrier Model
Molecular pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Abraham Al-ahmad, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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analysis of cancer targeting Alkylphosphocholine analogue permeability characteristics using a human induced pluripotent stem cell blood brain barrier model
Molecular Pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Abraham Alahmad, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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fluorescent cancer selective Alkylphosphocholine analogs for intraoperative glioma detection
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P<.01) than for CLR1501 (3.51±0.44 on confocal imaging; 7.23±1.63 on IVIS imaging) and 5-ALA (4.81±0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications. CONCLUSION CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor-to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery.
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Fluorescent cancer-selective Alkylphosphocholine analogs for intraoperative glioma detection.
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P
Jamey P. Weichert - One of the best experts on this subject based on the ideXlab platform.
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Diapeutic cancer-targeting Alkylphosphocholine analogs may advance management of brain malignancies.
CNS oncology, 2016Co-Authors: Ray R. Zhang, Kyle I. Swanson, Lance T. Hall, Jamey P. Weichert, John S. KuoAbstract:The following is a special report on Alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment in glioblastoma and brain metastases. These novel cancer-targeting agents display impressive tumor avidity with low background in the normal brain, and multimodal diagnostic imaging and therapy capabilities. The use of these agents may significantly improve diagnosis, treatment and post-treatment follow-up in patients with brain malignancies
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Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood–Brain Barrier Model
Molecular pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Abraham Al-ahmad, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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analysis of cancer targeting Alkylphosphocholine analogue permeability characteristics using a human induced pluripotent stem cell blood brain barrier model
Molecular Pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Abraham Alahmad, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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fluorescent cancer selective Alkylphosphocholine analogs for intraoperative glioma detection
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P<.01) than for CLR1501 (3.51±0.44 on confocal imaging; 7.23±1.63 on IVIS imaging) and 5-ALA (4.81±0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications. CONCLUSION CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor-to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery.
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Fluorescent cancer-selective Alkylphosphocholine analogs for intraoperative glioma detection.
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P
Verena Jendrossek - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy
Radiation oncology (London England), 2009Co-Authors: Guido Henke, Hansjörg Eibl, Lars H. Lindner, Michael Vogeser, Jürgen Wörner, Arndt Christian Müller, Michael Bamberg, Kirsten Wachholz, Claus Belka, Verena JendrossekAbstract:Background Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable Alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.
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Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy
Radiation Oncology, 2009Co-Authors: Guido Henke, Hansjörg Eibl, Lars H. Lindner, Michael Vogeser, Jürgen Wörner, Arndt Christian Müller, Michael Bamberg, Kirsten Wachholz, Claus Belka, Verena JendrossekAbstract:Background Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable Alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice. Methods NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity. Results Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (
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The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro
Radiation Oncology, 2006Co-Authors: Amelie Rübel, Hansjörg Eibl, Lars H. Lindner, Claus Belka, René Handrick, Matthias Steiger, Wilfried Budach, Verena JendrossekAbstract:Background Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable Alkylphosphocholine erucylphosphocholine (ErPC) is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro. ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine™ on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro.
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The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro
Radiation Oncology, 2006Co-Authors: Amelie Rübel, Hansjörg Eibl, Lars H. Lindner, Claus Belka, René Handrick, Matthias Steiger, Wilfried Budach, Verena JendrossekAbstract:Background Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable Alkylphosphocholine erucylphosphocholine (ErPC) is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro . ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine™ on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro . Results While all cell lines showed high intrinsic resistance against radiation-induced apoptosis as determined by fluorescence microscopy, treatment with ErPC and ErPC3 strongly increased sensitivity of the cells to radiation-induced cell death (apoptosis and necrosis). T98G cells were most responsive to the combined treatment revealing highly synergistic effects while A172 showed mostly additive to synergistic effects, and U87MG cells sub-additive, additive or synergistic effects, depending on the respective radiation-dose, drug-concentration and treatment time. Combined treatment enhanced therapy-induced damage of the mitochondria and caspase-activation. Importantly, combined treatment also increased radiation-induced eradication of clonogenic T98G cells as determined by standard colony formation assays. Conclusion Our observations make the combined treatment with ionizing radiation and the membrane targeted apoptosis modulators ErPC and ErPC3 a promising approach for the treatment of patients suffering from malignant glioma. The use of this innovative treatment concept in an in vivo xenograft setting is under current investigation.
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Induction of differentiation and tetraploidy by long-term treatment of C6 rat glioma cells with erucylphosphocholine.
International journal of oncology, 2001Co-Authors: Verena Jendrossek, Hansjörg Eibl, Wilfried Kugler, Bernhard Erdlenbruch, Max LakomekAbstract:Induction of differentiation represents a promising concept for chemotherapy of malignant gliomas, which are often refractory even to the combined treatment with surgery, irradiation and chemotherapy. Since anti-neoplastic Alkylphosphocholines can induce differentiation of leukemic cell lines, the effects of the intravenously applicable Alkylphosphocholine-derivative erucylphosphocholine (ErPC) on proliferation, morphology and differentiation of the rat glioma cell line C6 was examined in vitro. Short-term exposure to ErPC induced accumulation of the cells in the G2/M-phase of the cell cycle and apoptotic cell death. In contrast, continuous exposure of C6 rat glioma cells to sublethal ErPC doses (30 and 50 microM) caused both the formation of a slower growing tetraploid cell population and astrocytic differentiation. No resistance to in vivo obtainable ErPC concentrations was observed during this treatment. We conclude that ErPC-induced differentiation might be beneficial for a long-term adjuvant chemotherapy of low grade glioma.
Paul A. Clark - One of the best experts on this subject based on the ideXlab platform.
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Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood–Brain Barrier Model
Molecular pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Abraham Al-ahmad, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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analysis of cancer targeting Alkylphosphocholine analogue permeability characteristics using a human induced pluripotent stem cell blood brain barrier model
Molecular Pharmaceutics, 2016Co-Authors: Paul A. Clark, Ray R. Zhang, Jamey P. Weichert, John S. Kuo, Tongcheng Qian, Hannah K. Wilson, Sean P. Palecek, Abraham Alahmad, Eric V. ShustaAbstract:Cancer-targeting Alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure–activity studies. While they strongly label human brain cancers associated with disrupted blood–brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm2) and functional expression of drug efflux transporters. The radioiodinated an...
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fluorescent cancer selective Alkylphosphocholine analogs for intraoperative glioma detection
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P<.01) than for CLR1501 (3.51±0.44 on confocal imaging; 7.23±1.63 on IVIS imaging) and 5-ALA (4.81±0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high- contrast tumor visualization compatible with surgical applications. CONCLUSION CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor-to-brain fluorescence ratio similar to that of 5-ALA, whereas CLR1502 has a superior tumor-to-brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery.
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Fluorescent cancer-selective Alkylphosphocholine analogs for intraoperative glioma detection.
Neurosurgery, 2015Co-Authors: Kyle I. Swanson, Ray R. Zhang, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, John S. KuoAbstract:BACKGROUND 5-Aminolevulinic acid (5-ALA)-induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of 2 novel fluorescent, cancer-selective Alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. OBJECTIVE To demonstrate that CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and to compare tumor-to-normal brain (T:N) fluorescence ratios with 5-ALA. METHODS CLR1501, CLR1502, and 5-ALA were administered to mice with magnetic resonance imaging-verified orthotopic U251 glioblastoma multiforme- and glioblastoma stem cell-derived xenografts. Harvested brains were imaged with confocal microscopy (CLR1501), the IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or the Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. RESULTS Excitation/emission peaks are 500/517 nm for CLR1501 and 760/778 nm for CLR1502. The observed T:N ratio for CLR1502 (9.28±1.08) was significantly higher (P
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NOVEL Alkylphosphocholine ANALOGS FOR BROAD SPECTRUM CANCER IMAGING AND THERAPY
Neuro-Oncology, 2014Co-Authors: John S. Kuo, Jamey P. Weichert, Paul A. Clark, Irawati Kandela, Mohammed Farhoud, Marc Longino, Anatoly Pinchuk, Abram Vacaro, William Clark, Kyle I. SwansonAbstract:BACKGROUND: We present in vitro and in vivo imaging and therapeutic studies using a novel Alkylphosphocholine (APC)-based molecular scaffold (CLR1404) that combines selective targeting of cancer (including cancer stem cells) with broad-spectrum activity against many different cancer types. CLR1404 APC analogs were created to exploit the finding that phospholipid ethers selectively accumulate in many cancers versus normal cells. METHODS: Depending on the iodine isotope used, radioiodinated CLR1404 is either a PET imaging (124I) or molecular radiotherapeutic agent (131I), with fluorescence analogs created by replacing iodide with various fluorophores. Standard tissue culture, xenograft and molecular biology protocols were used for these studies. RESULTS: CLR1404 displayed preferential uptake and retention in cancer and cancer stem cells compared to normal cells in vitro and in vivo. After 24 hours, selective uptake of fluorescent or radioiodinated CLR1404 analogs by multiple human cancer cell lines in vitro compared to patient-matched normal human fibroblasts was observed (2.3-2.8x). CLR1404 showed highly specific labeling of both human patient-matched glioblastoma stem cells and serum-cultured glioblastoma cells (3x over minimal labeling of control normal human astrocytes and neural stem cells). Lipid raft disruption reduced in vitro CLR1404 analog uptake.In vivo, CLR1404 analogs displayed prolonged tumor-selective retention in 55 different rodent and human cancer models (including triple-negative breast, lung, pancreatic, colorectal, prostate, renal, melanoma, GBM). Tumor accumulation was seen by 24 hours with continued normal tissue clearance between 48-120 hours. In vivo cancer stem cell labeling was also demonstrated. CLR1404 analogs do not visualize inflammatory or premalignant lesions (unlike currently used 18F-fluorodeoxy glucose (FDG)-PET tumor imaging).131I-CLR1404 also displayed therapeutic efficacy (tumor growth suppression, survival extension) especially in renal, colorectal, ovarian, prostate and triple-negative breast cancer, GBM models. CONCLUSIONS: The novel APC CLR1404 analogs potentially offer a powerful multi- modality strategy to detect, treat and follow primary and metastatic cancers in humans. Initial clinical trials strongly suggest CLR1404 has similar broad tumor targeting and retention properties in animals and humans. The pathological correlation between CLR1404 imaging and GBM is being tested in an ongoing multi-institutional Phase II clinical trial. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.