Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects
Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 da...
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| creator | Nagaraja, Tavarekere N Aryal, Madhava P Brown, Stephen L Bagher-Ebadian, Hassan Mikkelsen, Tom Yang, James J Panda, Swayamprava Keenan, Kelly A Cabral, Glauber Ewing, James R |
| description | Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities. |
| doi_str_mv | 10.1371/journal.pone.0084493 |
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We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084493</identifier><identifier>PMID: 24376814</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute effects ; Analysis of Variance ; Anesthesiology ; Angiogenesis ; Animals ; Bioindicators ; Biomarkers ; Blood ; Blood Vessels - drug effects ; Blood Vessels - physiopathology ; Blood-brain barrier ; Blood-vessels ; Brain ; Brain cancer ; Brain tumors ; Cancer therapies ; Capillary Permeability - drug effects ; Chemotherapy, Adjuvant ; Concentration (composition) ; Contrast media ; Drugs ; Edema ; Glioma ; Glioma - blood supply ; Glioma - drug therapy ; Glioma - radiotherapy ; Gliomas ; Hospitals ; Immunohistochemistry ; Implantation ; Laboratory animals ; Magnetic Resonance Imaging ; Neurology ; NMR ; Nuclear magnetic resonance ; Parameter identification ; Peptides ; Perfusion ; Permeability ; Pharmacology ; Physics ; Potentiation ; Radiation therapy ; Rats ; Rats, Nude ; Sensitivity analysis ; Snake Venoms - pharmacology ; Temporal variations ; Time Factors ; Tumors ; Von Willebrand factor</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e84493-e84493</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Nagaraja et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Nagaraja et al 2013 Nagaraja et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-1ba585402b0bcda1868102a348fb37c3766c20f0b7633febeeb982d977fc38273</citedby><cites>FETCH-LOGICAL-c692t-1ba585402b0bcda1868102a348fb37c3766c20f0b7633febeeb982d977fc38273</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871527/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871527/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24376814$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Schlachetzki, Felix</contributor><creatorcontrib>Nagaraja, Tavarekere N</creatorcontrib><creatorcontrib>Aryal, Madhava P</creatorcontrib><creatorcontrib>Brown, Stephen L</creatorcontrib><creatorcontrib>Bagher-Ebadian, Hassan</creatorcontrib><creatorcontrib>Mikkelsen, Tom</creatorcontrib><creatorcontrib>Yang, James J</creatorcontrib><creatorcontrib>Panda, Swayamprava</creatorcontrib><creatorcontrib>Keenan, Kelly A</creatorcontrib><creatorcontrib>Cabral, Glauber</creatorcontrib><creatorcontrib>Ewing, James R</creatorcontrib><title>Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.</description><subject>Acute effects</subject><subject>Analysis of Variance</subject><subject>Anesthesiology</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Bioindicators</subject><subject>Biomarkers</subject><subject>Blood</subject><subject>Blood Vessels - drug effects</subject><subject>Blood Vessels - physiopathology</subject><subject>Blood-brain barrier</subject><subject>Blood-vessels</subject><subject>Brain</subject><subject>Brain cancer</subject><subject>Brain tumors</subject><subject>Cancer therapies</subject><subject>Capillary Permeability - drug effects</subject><subject>Chemotherapy, Adjuvant</subject><subject>Concentration (composition)</subject><subject>Contrast media</subject><subject>Drugs</subject><subject>Edema</subject><subject>Glioma</subject><subject>Glioma - blood 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Felix</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-23</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e84493</spage><epage>e84493</epage><pages>e84493-e84493</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24376814</pmid><doi>10.1371/journal.pone.0084493</doi><tpages>e84493</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-12, Vol.8 (12), p.e84493-e84493 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1470558709 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acute effects Analysis of Variance Anesthesiology Angiogenesis Animals Bioindicators Biomarkers Blood Blood Vessels - drug effects Blood Vessels - physiopathology Blood-brain barrier Blood-vessels Brain Brain cancer Brain tumors Cancer therapies Capillary Permeability - drug effects Chemotherapy, Adjuvant Concentration (composition) Contrast media Drugs Edema Glioma Glioma - blood supply Glioma - drug therapy Glioma - radiotherapy Gliomas Hospitals Immunohistochemistry Implantation Laboratory animals Magnetic Resonance Imaging Neurology NMR Nuclear magnetic resonance Parameter identification Peptides Perfusion Permeability Pharmacology Physics Potentiation Radiation therapy Rats Rats, Nude Sensitivity analysis Snake Venoms - pharmacology Temporal variations Time Factors Tumors Von Willebrand factor |
| title | Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T01%3A57%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cilengitide-induced%20temporal%20variations%20in%20transvascular%20transfer%20parameters%20of%20tumor%20vasculature%20in%20a%20rat%20glioma%20model:%20identifying%20potential%20MRI%20biomarkers%20of%20acute%20effects&rft.jtitle=PloS%20one&rft.au=Nagaraja,%20Tavarekere%20N&rft.date=2013-12-23&rft.volume=8&rft.issue=12&rft.spage=e84493&rft.epage=e84493&rft.pages=e84493-e84493&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0084493&rft_dat=%3Cgale_plos_%3EA478148856%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1470558709&rft_id=info:pmid/24376814&rft_galeid=A478148856&rft_doaj_id=oai_doaj_org_article_5c5e309437a64218b08009d325bfb174&rfr_iscdi=true |