Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate : Intravital microscopy and measurement of vascular permeability
The tumor vascular effects of the tubulin destabilizing agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumo...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2001-09, Vol.61 (17), p.6413-6422 |
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| creator | TOZER, Gillian M PRISE, Vivien E WILSON, John CEMAZAR, Maja SIQING SHAN DEWHIRST, Mark W BARBER, Paul R VOJNOVIC, Borivoj CHAPLIN, David J |
| description | The tumor vascular effects of the tubulin destabilizing agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using N(omega)-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to |
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CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using N(omega)-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to <5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-4-P and NOS inhibition was approximately additive. The mechanism of blood flow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute inflammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. The hematocrit within larger draining tumor venules tended to increase at early times after CA-4-P, suggesting fluid loss from the blood. The stacking of red cells to form rouleaux was also a common feature, coincident with slowing of blood flow; and these two factors would lead to an increase in viscous resistance to blood flow. Tumor vascular permeability to albumin was increased to approximately 160% of control values at 1 and 10 min after treatment. This could lead to an early decrease in tumor blood flow via an imbalance between intravascular and tissue pressures and/or an increase in blood viscosity as a result of increased hematocrit. These results suggest a mechanism of action of CA-4-P in vivo. Combination of CA-4-P with a NOS inhibitor has an additive effect, which it may be possible to exploit therapeutically.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 11522635</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Angiogenesis Inhibitors - pharmacology ; Animals ; Antineoplastic agents ; Antineoplastic Agents, Phytogenic - pharmacology ; Biological and medical sciences ; Capillary Permeability - drug effects ; Carcinosarcoma - blood supply ; Carcinosarcoma - drug therapy ; Carcinosarcoma - metabolism ; Chemotherapy ; Drug Synergism ; Enzyme Inhibitors - pharmacology ; Male ; Medical sciences ; Microscopy, Fluorescence - methods ; Neoplasms, Experimental - blood supply ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - metabolism ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - physiopathology ; Nitric Oxide - biosynthesis ; Nitric Oxide - physiology ; Nitric Oxide Synthase - antagonists & inhibitors ; Nitroarginine - pharmacology ; Pharmacology. Drug treatments ; Rats ; Stilbenes - pharmacology</subject><ispartof>Cancer research (Chicago, Ill.), 2001-09, Vol.61 (17), p.6413-6422</ispartof><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1123676$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11522635$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TOZER, Gillian M</creatorcontrib><creatorcontrib>PRISE, Vivien E</creatorcontrib><creatorcontrib>WILSON, John</creatorcontrib><creatorcontrib>CEMAZAR, Maja</creatorcontrib><creatorcontrib>SIQING SHAN</creatorcontrib><creatorcontrib>DEWHIRST, Mark W</creatorcontrib><creatorcontrib>BARBER, Paul R</creatorcontrib><creatorcontrib>VOJNOVIC, Borivoj</creatorcontrib><creatorcontrib>CHAPLIN, David J</creatorcontrib><title>Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate : Intravital microscopy and measurement of vascular permeability</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The tumor vascular effects of the tubulin destabilizing agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using N(omega)-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to <5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-4-P and NOS inhibition was approximately additive. The mechanism of blood flow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute inflammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. The hematocrit within larger draining tumor venules tended to increase at early times after CA-4-P, suggesting fluid loss from the blood. The stacking of red cells to form rouleaux was also a common feature, coincident with slowing of blood flow; and these two factors would lead to an increase in viscous resistance to blood flow. Tumor vascular permeability to albumin was increased to approximately 160% of control values at 1 and 10 min after treatment. This could lead to an early decrease in tumor blood flow via an imbalance between intravascular and tissue pressures and/or an increase in blood viscosity as a result of increased hematocrit. These results suggest a mechanism of action of CA-4-P in vivo. Combination of CA-4-P with a NOS inhibitor has an additive effect, which it may be possible to exploit therapeutically.</description><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Capillary Permeability - drug effects</subject><subject>Carcinosarcoma - blood supply</subject><subject>Carcinosarcoma - drug therapy</subject><subject>Carcinosarcoma - metabolism</subject><subject>Chemotherapy</subject><subject>Drug Synergism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microscopy, Fluorescence - methods</subject><subject>Neoplasms, Experimental - blood supply</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Neovascularization, Pathologic - physiopathology</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Nitric Oxide - physiology</subject><subject>Nitric Oxide Synthase - antagonists & inhibitors</subject><subject>Nitroarginine - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Stilbenes - pharmacology</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEtLAzEUhYMotlb_gmThdiDJJPNwV4qPguJG1-XmMUxkkgxJpqX_xR_rgBVdHe49H-dezhlaUlE2Rc25OEdLQkhTCF6zBbpK6XMeBSXiEi0oFYxVpViir1ejevA2uYQhpaAsZKPxweYe58mFiPeQ1DRAxKmfcqHDwWPr9aRmSh6xCk5GkyFlyNbjdcHx2Ic09nMMvsdbnyPsbYYBO6tiSCqMRwxeY2cgTdE44zMO3d-V0cTZknaw-XiNLjoYkrk56Qp9PD68b56Ll7en7Wb9UvSsJrloG8Ikl5JSzphoeVtBraAqqVStmJeV1qzrpGAUaFcTUoqKcVAtbzipSaXLFbr9yR0n6YzejdE6iMfdb00zcHcC5jdh6CJ4ZdM_jpVVXZXf3A50oQ</recordid><startdate>20010901</startdate><enddate>20010901</enddate><creator>TOZER, Gillian M</creator><creator>PRISE, Vivien E</creator><creator>WILSON, John</creator><creator>CEMAZAR, Maja</creator><creator>SIQING SHAN</creator><creator>DEWHIRST, Mark W</creator><creator>BARBER, Paul R</creator><creator>VOJNOVIC, Borivoj</creator><creator>CHAPLIN, David J</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20010901</creationdate><title>Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate : Intravital microscopy and measurement of vascular permeability</title><author>TOZER, Gillian M ; PRISE, Vivien E ; WILSON, John ; CEMAZAR, Maja ; SIQING SHAN ; DEWHIRST, Mark W ; BARBER, Paul R ; VOJNOVIC, Borivoj ; CHAPLIN, David J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h270t-9802b4bb1142259496a7ca631bc951146dd2ffb521a1f70035624ac94840706d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Capillary Permeability - drug effects</topic><topic>Carcinosarcoma - blood supply</topic><topic>Carcinosarcoma - drug therapy</topic><topic>Carcinosarcoma - metabolism</topic><topic>Chemotherapy</topic><topic>Drug Synergism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microscopy, Fluorescence - methods</topic><topic>Neoplasms, Experimental - blood supply</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - metabolism</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Neovascularization, Pathologic - physiopathology</topic><topic>Nitric Oxide - biosynthesis</topic><topic>Nitric Oxide - physiology</topic><topic>Nitric Oxide Synthase - antagonists & inhibitors</topic><topic>Nitroarginine - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Stilbenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TOZER, Gillian M</creatorcontrib><creatorcontrib>PRISE, Vivien E</creatorcontrib><creatorcontrib>WILSON, John</creatorcontrib><creatorcontrib>CEMAZAR, Maja</creatorcontrib><creatorcontrib>SIQING SHAN</creatorcontrib><creatorcontrib>DEWHIRST, Mark W</creatorcontrib><creatorcontrib>BARBER, Paul R</creatorcontrib><creatorcontrib>VOJNOVIC, Borivoj</creatorcontrib><creatorcontrib>CHAPLIN, David J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TOZER, Gillian M</au><au>PRISE, Vivien E</au><au>WILSON, John</au><au>CEMAZAR, Maja</au><au>SIQING SHAN</au><au>DEWHIRST, Mark W</au><au>BARBER, Paul R</au><au>VOJNOVIC, Borivoj</au><au>CHAPLIN, David J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate : Intravital microscopy and measurement of vascular permeability</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2001-09-01</date><risdate>2001</risdate><volume>61</volume><issue>17</issue><spage>6413</spage><epage>6422</epage><pages>6413-6422</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The tumor vascular effects of the tubulin destabilizing agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using N(omega)-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to <5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-4-P and NOS inhibition was approximately additive. The mechanism of blood flow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute inflammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. The hematocrit within larger draining tumor venules tended to increase at early times after CA-4-P, suggesting fluid loss from the blood. The stacking of red cells to form rouleaux was also a common feature, coincident with slowing of blood flow; and these two factors would lead to an increase in viscous resistance to blood flow. Tumor vascular permeability to albumin was increased to approximately 160% of control values at 1 and 10 min after treatment. This could lead to an early decrease in tumor blood flow via an imbalance between intravascular and tissue pressures and/or an increase in blood viscosity as a result of increased hematocrit. These results suggest a mechanism of action of CA-4-P in vivo. Combination of CA-4-P with a NOS inhibitor has an additive effect, which it may be possible to exploit therapeutically.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>11522635</pmid><tpages>10</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2001-09, Vol.61 (17), p.6413-6422 |
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| subjects | Angiogenesis Inhibitors - pharmacology Animals Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Capillary Permeability - drug effects Carcinosarcoma - blood supply Carcinosarcoma - drug therapy Carcinosarcoma - metabolism Chemotherapy Drug Synergism Enzyme Inhibitors - pharmacology Male Medical sciences Microscopy, Fluorescence - methods Neoplasms, Experimental - blood supply Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - physiopathology Nitric Oxide - biosynthesis Nitric Oxide - physiology Nitric Oxide Synthase - antagonists & inhibitors Nitroarginine - pharmacology Pharmacology. Drug treatments Rats Stilbenes - pharmacology |
| title | Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate : Intravital microscopy and measurement of vascular permeability |
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