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Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)
To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction. Female C3H/HeN mice be...
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| Published in: | Cancer chemotherapy and pharmacology 2003, Vol.51 (1), p.43-52 |
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| container_title | Cancer chemotherapy and pharmacology |
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| creator | SIIM, Bronwyn G LEE, Alan E SHALAL-ZWAIN, Sahar PRUIJN, Frederik B MCKEAGE, Mark J WILSON, William R |
| description | To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction.
Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain) |
| doi_str_mv | 10.1007/s00280-002-0529-0 |
| format | article |
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Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)<paclitaxel. The interaction with paclitaxel (31.6 micro mol/kg) was striking, with coadministration of DMXAA extending the median tumour growth delay from 0.3 to 80 days with three of seven animals cured. The interaction showed a broad timing of the optimum with similar activity when paclitaxel was administered 4 h before to 1 h after DMXAA: No therapeutic synergy was obtained when paclitaxel was combined with the antivascular agent combretastatin A4 phosphate (227 micro mol/kg), which induced only transient blood flow inhibition in this tumour, measured using the H33342 perfusion marker. Paclitaxel did not enhance the antivascular activity of DMXAA: Plasma and tumour concentrations of paclitaxel (and carboplatin), measured by LC-MS and ICP-MS respectively, were not elevated by combination with DMXAA:
There was a dramatic therapeutic interaction between DMXAA and standard chemotherapy drugs, particularly paclitaxel, against the MDAH-MCa-4 tumour, which was not due to a pharmacokinetic interaction or potentiation of antivascular activity. It is suggested that the major mechanism of synergy is killing of cells by DMXAA in poorly perfused regions of tumours that are inaccessible to chemotherapy drugs.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-002-0529-0</identifier><identifier>PMID: 12497205</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Bibenzyls - administration & dosage ; Biological and medical sciences ; Carboplatin - administration & dosage ; Chemotherapy ; Dose-Response Relationship, Drug ; Drug Synergism ; Female ; Mammary Neoplasms, Experimental - blood supply ; Mammary Neoplasms, Experimental - drug therapy ; Medical sciences ; Mice ; Mice, Inbred C3H ; Paclitaxel - administration & dosage ; Pharmacology. Drug treatments ; Stilbenes ; Time Factors ; Xanthenes - administration & dosage ; Xanthenes - pharmacokinetics ; Xanthenes - pharmacology ; Xanthones</subject><ispartof>Cancer chemotherapy and pharmacology, 2003, Vol.51 (1), p.43-52</ispartof><rights>2003 INIST-CNRS</rights><rights>Copyright Springer-Verlag 2003</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-d8acd1282fc617b25d0973facd9e30a8f593703e3d8ce38661ea6fa4b00ac3ad3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14598859$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12497205$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SIIM, Bronwyn G</creatorcontrib><creatorcontrib>LEE, Alan E</creatorcontrib><creatorcontrib>SHALAL-ZWAIN, Sahar</creatorcontrib><creatorcontrib>PRUIJN, Frederik B</creatorcontrib><creatorcontrib>MCKEAGE, Mark J</creatorcontrib><creatorcontrib>WILSON, William R</creatorcontrib><title>Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><description>To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction.
Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)<paclitaxel. The interaction with paclitaxel (31.6 micro mol/kg) was striking, with coadministration of DMXAA extending the median tumour growth delay from 0.3 to 80 days with three of seven animals cured. The interaction showed a broad timing of the optimum with similar activity when paclitaxel was administered 4 h before to 1 h after DMXAA: No therapeutic synergy was obtained when paclitaxel was combined with the antivascular agent combretastatin A4 phosphate (227 micro mol/kg), which induced only transient blood flow inhibition in this tumour, measured using the H33342 perfusion marker. Paclitaxel did not enhance the antivascular activity of DMXAA: Plasma and tumour concentrations of paclitaxel (and carboplatin), measured by LC-MS and ICP-MS respectively, were not elevated by combination with DMXAA:
There was a dramatic therapeutic interaction between DMXAA and standard chemotherapy drugs, particularly paclitaxel, against the MDAH-MCa-4 tumour, which was not due to a pharmacokinetic interaction or potentiation of antivascular activity. It is suggested that the major mechanism of synergy is killing of cells by DMXAA in poorly perfused regions of tumours that are inaccessible to chemotherapy drugs.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Bibenzyls - administration & dosage</subject><subject>Biological and medical sciences</subject><subject>Carboplatin - administration & dosage</subject><subject>Chemotherapy</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Mammary Neoplasms, Experimental - blood supply</subject><subject>Mammary Neoplasms, Experimental - drug therapy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Paclitaxel - administration & dosage</subject><subject>Pharmacology. Drug treatments</subject><subject>Stilbenes</subject><subject>Time Factors</subject><subject>Xanthenes - administration & dosage</subject><subject>Xanthenes - pharmacokinetics</subject><subject>Xanthenes - pharmacology</subject><subject>Xanthones</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><recordid>eNpFUdFqFDEUDVKx2-oH-FJCQbDQ6M0kmck8LrW1QosvCr6Fu0mmm3ZnZk0yxf0Kf9kMu9iXG3LvOecm5xDynsMnDtB8TgCVBlYqA1W1DF6RBZei3LQUR2QBQkqmGpDH5CSlRwCQXIg35JhXsm0qUAvy9x7jk3d0O2Y_5IA5jAMdO5rXnmJp5Kkfp0jR5vAc8m4e2bXvxzKPuPVTDpa6OD0kutr9Jz1jstMGC-2hiFJ1WTMXep_Xu82fMl_7YRw8kwytn_log6Mfv9z_Wi4v3pLXHW6Sf3c4T8nPm-sfV7fs7vvXb1fLO2aFkpk5jdbxSledrXmzqpSDthFdabZeAOpOtaIB4YXT1gtd19xj3aFcAaAV6MQpOd_rbuP4e_Ipm8fyz6GsNBUXsztKFBDfg2wcU4q-M9sYeow7w8HMCZh9AqZUMydgoHDODsLTqvfuhXGwvAA-HADFJdx0EQcb0gtOqlbr8vx_bYGQHw</recordid><startdate>2003</startdate><enddate>2003</enddate><creator>SIIM, Bronwyn G</creator><creator>LEE, Alan E</creator><creator>SHALAL-ZWAIN, Sahar</creator><creator>PRUIJN, Frederik B</creator><creator>MCKEAGE, Mark J</creator><creator>WILSON, William R</creator><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>2003</creationdate><title>Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)</title><author>SIIM, Bronwyn G ; LEE, Alan E ; SHALAL-ZWAIN, Sahar ; PRUIJN, Frederik B ; MCKEAGE, Mark J ; WILSON, William R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-d8acd1282fc617b25d0973facd9e30a8f593703e3d8ce38661ea6fa4b00ac3ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Bibenzyls - administration & dosage</topic><topic>Biological and medical sciences</topic><topic>Carboplatin - administration & dosage</topic><topic>Chemotherapy</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>Mammary Neoplasms, Experimental - blood supply</topic><topic>Mammary Neoplasms, Experimental - drug therapy</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Paclitaxel - administration & dosage</topic><topic>Pharmacology. Drug treatments</topic><topic>Stilbenes</topic><topic>Time Factors</topic><topic>Xanthenes - administration & dosage</topic><topic>Xanthenes - pharmacokinetics</topic><topic>Xanthenes - pharmacology</topic><topic>Xanthones</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SIIM, Bronwyn G</creatorcontrib><creatorcontrib>LEE, Alan E</creatorcontrib><creatorcontrib>SHALAL-ZWAIN, Sahar</creatorcontrib><creatorcontrib>PRUIJN, Frederik B</creatorcontrib><creatorcontrib>MCKEAGE, Mark J</creatorcontrib><creatorcontrib>WILSON, William R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SIIM, Bronwyn G</au><au>LEE, Alan E</au><au>SHALAL-ZWAIN, Sahar</au><au>PRUIJN, Frederik B</au><au>MCKEAGE, Mark J</au><au>WILSON, William R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2003</date><risdate>2003</risdate><volume>51</volume><issue>1</issue><spage>43</spage><epage>52</epage><pages>43-52</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction.
Female C3H/HeN mice bearing intramuscular MDAH-MCa-4 tumours were injected intraperitoneally with DMXAA (80 micro mol/kg) or chemotherapy drug (at a range up to the maximum tolerated dose) alone, or coadministered. A small reduction in the dose of the chemotherapy drug was required in most cases, but the increase in antitumour effect was much greater than the increase in host toxicity (body weight loss). The therapeutic gain increased in the order 5-fluorouracil (no gain)<(etoposide, carboplatin, cyclophosphamide, doxorubicin, cisplatin)<(docetaxel, vincristine)<paclitaxel. The interaction with paclitaxel (31.6 micro mol/kg) was striking, with coadministration of DMXAA extending the median tumour growth delay from 0.3 to 80 days with three of seven animals cured. The interaction showed a broad timing of the optimum with similar activity when paclitaxel was administered 4 h before to 1 h after DMXAA: No therapeutic synergy was obtained when paclitaxel was combined with the antivascular agent combretastatin A4 phosphate (227 micro mol/kg), which induced only transient blood flow inhibition in this tumour, measured using the H33342 perfusion marker. Paclitaxel did not enhance the antivascular activity of DMXAA: Plasma and tumour concentrations of paclitaxel (and carboplatin), measured by LC-MS and ICP-MS respectively, were not elevated by combination with DMXAA:
There was a dramatic therapeutic interaction between DMXAA and standard chemotherapy drugs, particularly paclitaxel, against the MDAH-MCa-4 tumour, which was not due to a pharmacokinetic interaction or potentiation of antivascular activity. It is suggested that the major mechanism of synergy is killing of cells by DMXAA in poorly perfused regions of tumours that are inaccessible to chemotherapy drugs.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>12497205</pmid><doi>10.1007/s00280-002-0529-0</doi><tpages>10</tpages></addata></record> |
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| identifier | ISSN: 0344-5704 |
| ispartof | Cancer chemotherapy and pharmacology, 2003, Vol.51 (1), p.43-52 |
| issn | 0344-5704 1432-0843 |
| language | eng |
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| source | Springer Nature |
| subjects | Animals Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bibenzyls - administration & dosage Biological and medical sciences Carboplatin - administration & dosage Chemotherapy Dose-Response Relationship, Drug Drug Synergism Female Mammary Neoplasms, Experimental - blood supply Mammary Neoplasms, Experimental - drug therapy Medical sciences Mice Mice, Inbred C3H Paclitaxel - administration & dosage Pharmacology. Drug treatments Stilbenes Time Factors Xanthenes - administration & dosage Xanthenes - pharmacokinetics Xanthenes - pharmacology Xanthones |
| title | Marked potentiation of the antitumour activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) |
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