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M C Bibby - One of the best experts on this subject based on the ideXlab platform.
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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, John W. Lippert, Patricia A. Cooper, M J Thompson, 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, John W. Lippert, Steve D. Shnyder, Patricia A. Cooper, K Grosios, 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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In vivo and in vitro evaluation of Combretastatin A-4 and its sodium phosphate prodrug.
British journal of cancer, 1999Co-Authors: K Grosios, Alan T Mcgown, S E Holwell, M C BibbyAbstract:The anti-tumour effects and mechanism of action of Combretastatin A-4 and its prodrug, Combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg–1, intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg–1, i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of Combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and β-tubulin at 1 h after treatment. In conclusion, Combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action. © 1999 Cancer Research Campaign
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in vivo and in vitro evaluation of Combretastatin a 4 and its sodium phosphate prodrug
British Journal of Cancer, 1999Co-Authors: K Grosios, Alan T Mcgown, S E Holwell, M C BibbyAbstract:The anti-tumour effects and mechanism of action of Combretastatin A-4 and its prodrug, Combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg–1, intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg–1, i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of Combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and β-tubulin at 1 h after treatment. In conclusion, Combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action. © 1999 Cancer Research Campaign
Mouad Alami - One of the best experts on this subject based on the ideXlab platform.
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Regioselective Hydrostannation of Diarylalkynes Directed by a Labile ortho Bromine Atom: An Easy Access to Stereodefined Triarylolefins, Hybrids of Combretastatin A-4 and IsoCombretastatin A-4.
ChemInform, 2010Co-Authors: Evelia Rasolofonjatovo, Olivier Provot, Abdallah Hamze, Jérôme Bignon, Sylviane Thoret, Jean-daniel Brion, Mouad AlamiAbstract:A series of 7 triarylolefins of type (VII) or (VIII) bearing the Combretastatin A-4 and isoCombretastatin A-4 core are prepared.
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Regioselective hydrostannation of diarylalkynes directed by a labile ortho bromine atom: an easy access to stereodefined triarylolefins, hybrids of Combretastatin A-4 and isoCombretastatin A-4.
European journal of medicinal chemistry, 2010Co-Authors: Evelia Rasolofonjatovo, Olivier Provot, Abdallah Hamze, Jérôme Bignon, Sylviane Thoret, Jean-daniel Brion, Mouad AlamiAbstract:A series of triarylolefins bearing the Combretastatin A-4 and the isoCombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.
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Synthetic approach to enyne and enediyne analogues of anticancer agents
Tetrahedron Letters, 2005Co-Authors: Olivier Provot, Mouad Alami, Anne Giraud, Jean-françois Peyrat, Jean-daniel BrionAbstract:The synthesis and the anticancer activity of a new kind of enynes 2 and 3 and enediynes 4, analogues of Combretastatin A-4 1 are reported and discussed.
Jens Overgaard - One of the best experts on this subject based on the ideXlab platform.
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Combretastatins novel vascular targeting drugs for improving anti cancer therapy Combretastatins and conventional therapy
Advances in Experimental Medicine and Biology, 2000Co-Authors: Michael R. Horsman, Rumi Murata, T Breidahl, F U Nielsen, R J Maxwell, H Stodkiledjorgensen, Jens OvergaardAbstract:Combretastatins are a new class of compounds that appear to have anti-tumour activity as a result of specifically targeting the vasculature of tumours. The aim of this study was to investigate the potential of Combretastatin A-4 disodium phosphate (CA4DP) to induce vascular effects in a C3H mouse mammary carcinoma, and to see if the anti-tumour response could be improved by combining the drug with conventional anti-cancer therapies. It was found that CA4DP (250 mg/kg) significantly decreased tumour perfusion within 30 minutes after injection and maintained this decrease for several hours, although there was a return to normal by 24 hours. Similar changes were seen in the tumours bioenergetic and oxygenation status. The drug also significantly increased tumour necrosis and had a small inhibitory effect on tumour growth. It was also able to enhance the tumour response to radiation and hyperthermia, when given at the same time or 30 minutes after the radiation and hyperthermia, respectively. Giving the drug 1 hour after cisplatin injection only resulted in a tumour response that was no greater than additive. These results confirm the anti-vascular effects of CA4DP and demonstrate its potential to enhance the anti-tumour activity of conventional therapy.
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Combretastatins novel vascular targeting drugs for improving anticancer therapy
2000Co-Authors: Michael R. Horsman, Rumi Murata, T Breidahl, F U Nielsen, R J Maxwell, H Stodkiledjorgensen, Jens OvergaardAbstract:Combretastatins are a new class of compounds that appear to have antitumour activity as a result of specifically targeting the vasculature of tumours. The aim of this study was to investigate the potential of Combretastatin A-4 disodium phosphate (CA4DP) to induce vascular effects in a C3H mouse mammary carcinoma, and to see if the anti-tumour response could be improved by combining the drug with conventional anticancer therapies. It was found that CA4DP (250 mg/kg) significantly decreased tumour perfusion within 30 minutes after injection and maintained this decrease for several hours, although there was a return to normal by 24 hours. Similar changes were seen in the tumours bioenergetic and oxygenation status. The drug also significantly increased tumour necrosis and had a small inhibitory effect on tumour growth. It was also able to enhance the tumour response to radiation and hyperthermia, when given at the same time or 30 minutes after the radiation and hyperthermia, respectively. Giving the drug 1 hour after cisplatin injection only resulted in a tumour response that was no greater than additive. These results confirm the anti-vascular effects of CA4DP and demonstrate its potential to enhance the anti-tumour activity of conventional therapy.
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the effect of Combretastatin a 4 disodium phosphate in a c3h mouse mammary carcinoma and a variety of murine spontaneous tumors
International Journal of Radiation Oncology Biology Physics, 1998Co-Authors: Michael R. Horsman, Eva Ehrnrooth, Morten Ladekarl, Jens OvergaardAbstract:Purpose: To investigate the activity of Combretastatin A-4 disodium phosphate in a transplanted C3H mouse mammary carcinoma and several murine spontaneous tumors. Methods and Materials: The C3H mammary carcinoma was grown in the right rear foot of female CDF1 mice and treated when 200 mm3 in size. Spontaneous tumors (341–1437 mm3 in size) arose at different sites in female CDF1 mice that, 19–21 months earlier, had been irradiated. Oxygen partial pressure (pO2) distributions in the C3H tumors were measured with an Eppendorf oxygen electrode at various times after injecting Combretastatin (100 mg/kg, i.p.) in restrained, nonanesthetized mice. Immediately after measurement, tumors were excised and necrotic fraction determined from histological sections. In the spontaneous tumors, pO2 was measured before and 3 h after giving Combretastatin. The location of these spontaneous tumors required that measurements be made in anesthetised animals, achieved by injecting a mixture of hypnorm and diazepam. Results: In untreated C3H tumors, the mean (± 1 SE) percentage of pO2 values ≤ 2.5 mmHg was 32% (± 11). This was significantly (Student’s t-test; p < 0.05) increased to 74% (± 4) within 1 h after injecting Combretastatin, and remained at this level for at least 6 h, although some recovery was seen at 12 and 24 h. The necrotic fraction in control tumors was 1.9% (± 0.4) and this was significantly increased to 16.1% (± 3.7) 24 h after drug administration. In spontaneous tumors, the pO2 measurements indicated that 5 of 6 showed some response to Combretastatin, although the degree of change was variable. Conclusions: Combretastatin increased tumor hypoxia and necrosis in the C3H mammary carcinoma, consistent with the induction of vascular damage. Drug-induced changes in pO2 were also found in spontaneous tumors, suggesting that the activity of this drug is not restricted to transplanted tumors alone.
Sally A. Hill - One of the best experts on this subject based on the ideXlab platform.
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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.
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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, 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.
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Anti-vascular approaches to solid tumour therapy: evaluation of Combretastatin A4 phosphate.
Anticancer research, 1999Co-Authors: Dai J. Chaplin, Sally A. HillAbstract:Abstract Combretastatin A4 phosphate has recently been identified by us as an agent which can selectively damage tumour neovasculature. In the current study we establish that Combretastatin induces extensive blood flow shutdown in the tumour compared to normal tissues. Histological assessment of vascular shutdown shows that over 90% of vessels are rendered non-functional 6 hrs post-treatment with 100 mg/kg i.p. Measurement of blood flow using a diffusible tracer 86RbCl indicates an overall reduction in perfusion by only 50-60%. This discrepancy probably reflects increased blood flow in the normal tissue vasculature supplying the tumour rim, which is caused by the ischaemia-induced release of vasoactive mediators. The vascular shutdown induced by administration of 100 mg/kg of Combretastatin A4 phosphate results in extensive cell loss in the 24 hrs following treatment, however this is not translated into any significant effect on tumour growth. The continued growth of the tumour is attributed to an actively proliferating population of cells at the periphery of the tumour, which are dependent on normal tissue vasculature for their survival. We have attempted to target this residual population by combining Combretastatin A4 phosphate with cytotoxic approaches. Cis platinum and radiation have been used. The results show that Combretastatin can significantly enhance tumour response to both cis platinum and radiation. In summary, the studies confirm Combretastatin A4 phosphate as a novel agent which targets and damages tumour vasculature and, moreover, indicate its potential therapeutic usefulness as an adjuvant to conventional cytotoxic approaches.
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Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents.
The British journal of cancer. Supplement, 1996Co-Authors: D J Chaplin, C S Parkins, Sally A. HillAbstract:We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15, Combretastatin A1 and Combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with Combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine. Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour cells induced as a consequence of blood flow reduction.
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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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.