Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs
Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro . Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug deli...
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| Veröffentlicht in: | Clinical cancer research 2008-06, Vol.14 (12), p.3926-3932 |
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| creator | BHATTACHARYA, Arup SESHADRI, Mukund OVEN, Steven D TOTH, Karoly VAUGHAN, Mary M RUSTUM, Youcef M |
| description | Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and
anticancer drugs could not be shown in vitro . Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery
in the observed therapeutic synergy in vivo .
Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally).
Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC 7 ), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment
period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin
using high-performance liquid chromatography and fluorescence microscopy.
Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth
inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% > control) indicative
of increased pericyte coverage of microvessels. Hoechst 33342/DiOC 7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular
contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent
with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared
with administration of doxorubicin alone.
Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation
in vivo , and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo . |
| doi_str_mv | 10.1158/1078-0432.CCR-08-0212 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2504718</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19476328</sourcerecordid><originalsourceid>FETCH-LOGICAL-c504t-41bf901815f125d6f8c7901e80dc5977d9836a0c13281bed01c743e86abeebb43</originalsourceid><addsrcrecordid>eNpVkd2O0zAQhSMEYn_gEUC-AYmLLB7HTpwbpFWXn0pdIUHh1nKcSWOU2sVOusoT7Gvj0rLAlY_H35yx5mTZC6BXAEK-BVrJnPKCXS0WX3KaNAP2KDsHIaq8YKV4nPQf5iy7iPEHpcCB8qfZGUgh6hL4eXa_nrY-kO86mmnQgdzqcQp6tN4R7Vqy3O6C32NLbsK0ITc42D2GmSxdO5lUbWZyi2M_DxEHdN7McUTrkKxQt5GMnqx7DHqH02gN-To7DJuZ3NmxJ9culbQzGH5bx2fZk04nm-en8zL79uH9evEpX33-uFxcr3IjKB9zDk1XU5AgOmCiLTtpqnRHSVsj6qpqa1mUmhoomIQGWwqm4gXKUjeITcOLy-zd0Xc3NVtsDbox6EHtgt3qMCuvrfr_xdlebfxesTS_ApkMXp8Mgv85YRzV1kaDw6Ad-ikqqHlVpukJFEfQBB9jwO5hCFB1iFAd4lGHeFSKUNGkU4Sp7-W_P_zbdcosAa9OQApND11Ia7TxgWOUS8lkmbg3R663m_7OBlTHhQeMqIPpFXAFTBU1K4tfAjq2dw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19476328</pqid></control><display><type>article</type><title>Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>American Association for Cancer Research</source><source>Alma/SFX Local Collection</source><creator>BHATTACHARYA, Arup ; SESHADRI, Mukund ; OVEN, Steven D ; TOTH, Karoly ; VAUGHAN, Mary M ; RUSTUM, Youcef M</creator><creatorcontrib>BHATTACHARYA, Arup ; SESHADRI, Mukund ; OVEN, Steven D ; TOTH, Karoly ; VAUGHAN, Mary M ; RUSTUM, Youcef M</creatorcontrib><description>Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and
anticancer drugs could not be shown in vitro . Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery
in the observed therapeutic synergy in vivo .
Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally).
Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC 7 ), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment
period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin
using high-performance liquid chromatography and fluorescence microscopy.
Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth
inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% > control) indicative
of increased pericyte coverage of microvessels. Hoechst 33342/DiOC 7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular
contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent
with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared
with administration of doxorubicin alone.
Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation
in vivo , and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo .</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-08-0212</identifier><identifier>PMID: 18559614</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; antiangiogenic agent ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Capillary Permeability - drug effects ; Carcinoma, Squamous Cell - blood supply ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - pathology ; Cysteine - administration & dosage ; Cysteine - analogs & derivatives ; drug delivery ; Drug Delivery Systems ; Drug Synergism ; Female ; Head and Neck Neoplasms - blood supply ; Head and Neck Neoplasms - drug therapy ; Head and Neck Neoplasms - pathology ; Humans ; Medical sciences ; methylselenocysteine ; Mice ; Mice, Nude ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - pathology ; Organoselenium Compounds - administration & dosage ; Pharmacology. Drug treatments ; selenium ; Selenocysteine - analogs & derivatives ; vascular maturation ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2008-06, Vol.14 (12), p.3926-3932</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-41bf901815f125d6f8c7901e80dc5977d9836a0c13281bed01c743e86abeebb43</citedby><cites>FETCH-LOGICAL-c504t-41bf901815f125d6f8c7901e80dc5977d9836a0c13281bed01c743e86abeebb43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,3358,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20488286$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18559614$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BHATTACHARYA, Arup</creatorcontrib><creatorcontrib>SESHADRI, Mukund</creatorcontrib><creatorcontrib>OVEN, Steven D</creatorcontrib><creatorcontrib>TOTH, Karoly</creatorcontrib><creatorcontrib>VAUGHAN, Mary M</creatorcontrib><creatorcontrib>RUSTUM, Youcef M</creatorcontrib><title>Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and
anticancer drugs could not be shown in vitro . Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery
in the observed therapeutic synergy in vivo .
Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally).
Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC 7 ), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment
period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin
using high-performance liquid chromatography and fluorescence microscopy.
Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth
inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% > control) indicative
of increased pericyte coverage of microvessels. Hoechst 33342/DiOC 7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular
contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent
with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared
with administration of doxorubicin alone.
Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation
in vivo , and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo .</description><subject>Animals</subject><subject>antiangiogenic agent</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Capillary Permeability - drug effects</subject><subject>Carcinoma, Squamous Cell - blood supply</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cysteine - administration & dosage</subject><subject>Cysteine - analogs & derivatives</subject><subject>drug delivery</subject><subject>Drug Delivery Systems</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>Head and Neck Neoplasms - blood supply</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>methylselenocysteine</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Organoselenium Compounds - administration & dosage</subject><subject>Pharmacology. Drug treatments</subject><subject>selenium</subject><subject>Selenocysteine - analogs & derivatives</subject><subject>vascular maturation</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd2O0zAQhSMEYn_gEUC-AYmLLB7HTpwbpFWXn0pdIUHh1nKcSWOU2sVOusoT7Gvj0rLAlY_H35yx5mTZC6BXAEK-BVrJnPKCXS0WX3KaNAP2KDsHIaq8YKV4nPQf5iy7iPEHpcCB8qfZGUgh6hL4eXa_nrY-kO86mmnQgdzqcQp6tN4R7Vqy3O6C32NLbsK0ITc42D2GmSxdO5lUbWZyi2M_DxEHdN7McUTrkKxQt5GMnqx7DHqH02gN-To7DJuZ3NmxJ9culbQzGH5bx2fZk04nm-en8zL79uH9evEpX33-uFxcr3IjKB9zDk1XU5AgOmCiLTtpqnRHSVsj6qpqa1mUmhoomIQGWwqm4gXKUjeITcOLy-zd0Xc3NVtsDbox6EHtgt3qMCuvrfr_xdlebfxesTS_ApkMXp8Mgv85YRzV1kaDw6Ad-ikqqHlVpukJFEfQBB9jwO5hCFB1iFAd4lGHeFSKUNGkU4Sp7-W_P_zbdcosAa9OQApND11Ia7TxgWOUS8lkmbg3R663m_7OBlTHhQeMqIPpFXAFTBU1K4tfAjq2dw</recordid><startdate>20080615</startdate><enddate>20080615</enddate><creator>BHATTACHARYA, Arup</creator><creator>SESHADRI, Mukund</creator><creator>OVEN, Steven D</creator><creator>TOTH, Karoly</creator><creator>VAUGHAN, Mary M</creator><creator>RUSTUM, Youcef M</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><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20080615</creationdate><title>Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs</title><author>BHATTACHARYA, Arup ; SESHADRI, Mukund ; OVEN, Steven D ; TOTH, Karoly ; VAUGHAN, Mary M ; RUSTUM, Youcef M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-41bf901815f125d6f8c7901e80dc5977d9836a0c13281bed01c743e86abeebb43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>antiangiogenic agent</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Capillary Permeability - drug effects</topic><topic>Carcinoma, Squamous Cell - blood supply</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cysteine - administration & dosage</topic><topic>Cysteine - analogs & derivatives</topic><topic>drug delivery</topic><topic>Drug Delivery Systems</topic><topic>Drug Synergism</topic><topic>Female</topic><topic>Head and Neck Neoplasms - blood supply</topic><topic>Head and Neck Neoplasms - drug therapy</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>methylselenocysteine</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Organoselenium Compounds - administration & dosage</topic><topic>Pharmacology. Drug treatments</topic><topic>selenium</topic><topic>Selenocysteine - analogs & derivatives</topic><topic>vascular maturation</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BHATTACHARYA, Arup</creatorcontrib><creatorcontrib>SESHADRI, Mukund</creatorcontrib><creatorcontrib>OVEN, Steven D</creatorcontrib><creatorcontrib>TOTH, Karoly</creatorcontrib><creatorcontrib>VAUGHAN, Mary M</creatorcontrib><creatorcontrib>RUSTUM, Youcef M</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BHATTACHARYA, Arup</au><au>SESHADRI, Mukund</au><au>OVEN, Steven D</au><au>TOTH, Karoly</au><au>VAUGHAN, Mary M</au><au>RUSTUM, Youcef M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2008-06-15</date><risdate>2008</risdate><volume>14</volume><issue>12</issue><spage>3926</spage><epage>3932</epage><pages>3926-3932</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and
anticancer drugs could not be shown in vitro . Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery
in the observed therapeutic synergy in vivo .
Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally).
Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC 7 ), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment
period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin
using high-performance liquid chromatography and fluorescence microscopy.
Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth
inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% > control) indicative
of increased pericyte coverage of microvessels. Hoechst 33342/DiOC 7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular
contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent
with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared
with administration of doxorubicin alone.
Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation
in vivo , and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo .</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>18559614</pmid><doi>10.1158/1078-0432.CCR-08-0212</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2008-06, Vol.14 (12), p.3926-3932 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection |
| subjects | Animals antiangiogenic agent Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Capillary Permeability - drug effects Carcinoma, Squamous Cell - blood supply Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - pathology Cysteine - administration & dosage Cysteine - analogs & derivatives drug delivery Drug Delivery Systems Drug Synergism Female Head and Neck Neoplasms - blood supply Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - pathology Humans Medical sciences methylselenocysteine Mice Mice, Nude Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - pathology Organoselenium Compounds - administration & dosage Pharmacology. Drug treatments selenium Selenocysteine - analogs & derivatives vascular maturation Xenograft Model Antitumor Assays |
| title | Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs |
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