The Experts below are selected from a list of 4404 Experts worldwide ranked by ideXlab platform
Gillian M. Tozer - One of the best experts on this subject based on the ideXlab platform.
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Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4
Journal of medicinal chemistry, 2016Co-Authors: Andrew W. Brown, Gillian M. Tozer, Matthew Fisher, Chryso Kanthou, Joseph P. A. HarrityAbstract:The Combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor vascular disrupting agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to β-tubulin, believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis.
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Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4
2016Co-Authors: Andrew W. Brown, Gillian M. Tozer, Matthew Fisher, Chryso Kanthou, Joseph P. A. HarrityAbstract:The Combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor vascular disrupting agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to β-tubulin, believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate protein induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the Combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of protein induction following treatment could yield insights into resistance mechanisms. The distribution of a number of proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified proteins to their functional partners.
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the biology of the Combretastatins as tumour vascular targeting agents
International Journal of Experimental Pathology, 2002Co-Authors: Gillian M. Tozer, Chryso Kanthou, C S Parkins, Sally A. HillAbstract:The tumour vasculature is an attractive target for therapy. Combretastatin A-4 (CA-4) and A-1 (CA-1) are tubulin binding agents, structurally related to colchicine, which induce vascular-mediated tumour necrosis in animal models. CA-1 and CA-4 were isolated from the African bush willow, Combretum caffrum, and several synthetic analogues are also now available, such as the Aventis Pharma compound, AVE8062. More soluble, phosphated, forms of CA-4 (CA-4-P) and CA-1 (CA-1-P) are commonly used for in vitro and in vivo studies. These are cleaved to the natural forms by endogenous phosphatases and are taken up into cells. The lead compound, CA-4-P, is currently in clinical trial as a tumour vascular targeting agent. In animal models, CA-4-P causes a prolonged and extensive shut-down of blood flow in established tumour blood vessels, with much less effect in normal tissues. This paper reviews the current understanding of the mechanism of action of the Combretastatins and their therapeutic potential.
Malcolm R. Clench - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate protein induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the Combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of protein induction following treatment could yield insights into resistance mechanisms. The distribution of a number of proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified proteins to their functional partners.
Laura M. Cole - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate protein induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the Combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of protein induction following treatment could yield insights into resistance mechanisms. The distribution of a number of proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified proteins to their functional partners.
George R Pettit - One of the best experts on this subject based on the ideXlab platform.
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an efficient synthetic strategy for obtaining 4 methoxy carbon isotope labeled combretastatin a 4 phosphate and other z Combretastatins
Journal of Natural Products, 2010Co-Authors: George R Pettit, Fiona Hogan, Mathew D Minardi, P B PriceAbstract:Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [11C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [11C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.
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Antineoplastic agents. 565. Synthesis of combretastatin D-2 phosphate and dihydro-combretastatin D-2.
Journal of natural products, 2009Co-Authors: George R Pettit, Ernest Hamel, Delbert L. Herald, Peter D. Quistorf, Jeremy A. Fry, Jean-charles ChapuisAbstract:A modified synthetic route to combretastatin D-2 (5) was devised in order to further evaluate its biological activity, for its conversion to phosphate prodrugs (25-28), and as a route to obtaining dihydro-combretastatin D-2 (42). A parallel first total synthesis of dihydro-combretastatin D-2 was completed, proceeding from a saturated 3-phenylpropionic ester intermediate via the Ullmann biaryl ether reaction (39-41). In contrast to the cancer cell growth inhibitory activity exhibited by combretastatin D-2, relatively minor structural modifications (41, 42) caused elimination of those properties.
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anti tumor and anti vascular effects of the novel tubulin binding agent combretastatin a 1 phosphate
Anticancer Research, 2002Co-Authors: S E Holwell, George R Pettit, Patricia A Cooper, M J Thompson, John W Lippert, Sandie W Martin, M C BibbyAbstract:The Combretastatins are derived from an African medicinal plant Combretum caffrum (Combretaceae). They have previously been shown to be potent inhibitors of microtubule assembly that cause marked haemorrhagic necrosis in murine subcutaneous tumors. Promising clinical trial results with combretastatin A-4 phosphate led to this investigation of the anti-tumor and anti-vascular effects of a close structural analog, combretastatin A-1 phosphate. This compound caused identical disruption of the tubulin cytoskeleton in HUVECs in vitro at similar concentrations and duration of exposure as combretastatin A-4 phosphate. Treatment of a well-vascularised murine colon adenocarcinoma (MAC 29) with an effective dose (150 mg/kg) of combretastatin A-1 phosphate resulted in a dramatic decrease in functional vascular volume 2 hours after administration. Vascular shutdown was complete within 4 hours after treatment apart from in small areas of the tumor periphery. Morphological examination of hepatic deposits of HT29 and DLD-1 human colon tumors in nude mice demonstrated that combretastatin A-1 phosphate displays greater anti-tumor effects than the A-4 analog at the same dose and this order of activity (A-1 > A-4) is mirrored in the subcutaneous site with the same tumor type. In summary, combretastatin A-1 phosphate can exert its anti-tumor action via an anti-vascular mechanism. The results indicate that, despite having similar in vitro anti-tubulin properties, combretastatin A-1 phosphate seems to have greater in vivo anti-tumor activity than combretastatin A-4 phosphate at the same doses and may therefore be more successful in the clinic.
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combretastatin a 1 phosphate a novel tubulin binding agent with in vivo anti vascular effects in experimental tumours
Anticancer Research, 2002Co-Authors: S E Holwell, George R Pettit, Patricia A Cooper, John W Lippert, K Grosios, Steven D Shnyder, M C BibbyAbstract:In view of the clinical potential of a number of natural products, Combretastatin A-1 phosphate was developed as a water-soluble derivative of combretastatin A-1. This study examined the anti-tumour activity of this compound against an experimental colon tumour (MAC29) in mice. A comparison was made with the clinically active combretastatin A-4 phosphate. The new compound was well-tolerated up to a dose of 250 mg/kg and was more effective at producing tumour growth delays than the A-4 analogue. Significant growth delays were seen at a dose of 50 mg/kg whereas the A-4 phosphate produced no measurable growth delay until a dose of 150 mg/kg was administered. Histological examination of treated tumours indicated that combretastatin A-1 phosphate caused very severe haemorrhagic necrosis in the tumour tissue and analysis of the sections indicated that almost 94 percent of the tumour was dead within 24 hours of treatment. The mechanism of action of combretastatin A-1 phosphate appears to be similar to the A-4 phosphate in that tumour vascular shutdown occurs within 4 hours of treatment. In summary combretastatin A-1 phosphate, the water-soluble analogue of combretastatin A-1, is more potent against a well-vascularised murine colon tumour than its predecessor, combretastatin A-4 phosphate. These data suggest this compound may have potential for clinical development.
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Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503.
Anticancer research, 2002Co-Authors: Sally A. Hill, George R Pettit, Gillian M Toze, David J. ChaplinAbstract:BACKGROUND Tubulin depolymerizing drugs, which selectively disrupt tumour neovasculature, have recently been identified. The lead drug in this class, combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. We have continued to synthesize and evaluate a number of Combretastatins, with the aim of identifying novel agents that possess single agent activity. In the studies presented here we provide data on our lead preclinical compound and compare its antivascular and antitumour activity to that of CA4P in the murine breast adenocarcinoma CaNT. This compound, designated Oxi 4503, is the diphosphate prodrug form of combretastatin A1. RESULTS At a dose of 1 mg/kg Oxi 4503 induced a greater than 50% reduction in functional vascular volume, which increased to 80% or more following doses of 10, 25 and 50 mg/kg. In contrast, CA4P induced approximately 40% vascular shutdown at 50 mg/kg, but had no measurable effect at 10 mg/kg. In addition to these vascular effects, Oxi 4503 at doses of 100, 200 and 400 mg/kg induced significant retardation in the growth of established CaNT tumours. No significant growth retardation was obtained with single doses of up to 400 mg/kg CA4P. CONCLUSION In summary, these studies have identified Oxi 4503 as a preclinical development candidate with more potent antivascular and antitumour effects than CA4P when used as a single agent.
Martyn N.j. Paley - One of the best experts on this subject based on the ideXlab platform.
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MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate protein induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent.
Proteomics, 2014Co-Authors: Laura M. Cole, Joanne E. Bluff, Vikki A. Carolan, Martyn N.j. Paley, Gillian M. Tozer, Malcolm R. ClenchAbstract:Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the Combretastatins form the largest group of tumour vascular disrupting agents and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response biomarkers are required for personalising treatment planning. Protein induction following treatment with combretastatin A4-phosphate was examined in a mouse fibrosarcoma model (fs188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by combretastatin A4-phosphate and hence a study of protein induction following treatment could yield insights into resistance mechanisms. The distribution of a number of proteins induced following treatment were visualised by MALDI-mass spectrometry imaging. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical staining. Significant changes in proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified proteins to their functional partners.