Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study
Identifieur interne : 002277 ( Pmc/Curation ); précédent : 002276; suivant : 002278Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study
Auteurs : Eddy Pasquier [France, Australie] ; Nicolas André [France] ; Janine Street [Australie] ; Anuradha Chougule [Inde] ; Bharat Rekhi [Inde] ; Jaya Ghosh [Inde] ; Deepa S. J. Philip [Inde] ; Marie Meurer [France] ; Karen L. Mackenzie [Australie] ; Maria Kavallaris [Australie] ; Shripad D. Banavali [France, Inde]Source :
- EBioMedicine [ 2352-3964 ] ; 2016.
Abstract
Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.
Gene expression analysis showed expression of
Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.
This study was funded by institutional and philanthropic grants.
Url:
DOI: 10.1016/j.ebiom.2016.02.026
PubMed: 27211551
PubMed Central: 4856748
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Philip</name><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author><author><name sortKey="Meurer, Marie" sort="Meurer, Marie" uniqKey="Meurer M" first="Marie" last="Meurer">Marie Meurer</name><affiliation wicri:level="1"><nlm:aff id="af0005">INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0035">Service d'Oncologie Médicale, AP-HM, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Service d'Oncologie Médicale, AP-HM, Marseille</wicri:regionArea></affiliation></author><author><name sortKey="Mackenzie, Karen L" sort="Mackenzie, Karen L" uniqKey="Mackenzie K" first="Karen L." last="Mackenzie">Karen L. Mackenzie</name><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Kavallaris, Maria" sort="Kavallaris, Maria" uniqKey="Kavallaris M" first="Maria" last="Kavallaris">Maria Kavallaris</name><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0040">Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney</wicri:regionArea></affiliation></author><author><name sortKey="Banavali, Shripad D" sort="Banavali, Shripad D" uniqKey="Banavali S" first="Shripad D." last="Banavali">Shripad D. Banavali</name><affiliation wicri:level="1"><nlm:aff id="af0010">Metronomics Global Health Initiative, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Metronomics Global Health Initiative, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27211551</idno><idno type="pmc">4856748</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856748</idno><idno type="RBID">PMC:4856748</idno><idno type="doi">10.1016/j.ebiom.2016.02.026</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002427</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" 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id="af0010">Metronomics Global Health Initiative, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Metronomics Global Health Initiative, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Andre, Nicolas" sort="Andre, Nicolas" uniqKey="Andre N" first="Nicolas" last="André">Nicolas André</name><affiliation wicri:level="1"><nlm:aff id="af0005">INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0010">Metronomics Global Health Initiative, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Metronomics Global Health Initiative, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0020">Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille</wicri:regionArea></affiliation></author><author><name sortKey="Street, Janine" sort="Street, Janine" uniqKey="Street J" first="Janine" last="Street">Janine Street</name><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Chougule, Anuradha" sort="Chougule, Anuradha" uniqKey="Chougule A" first="Anuradha" last="Chougule">Anuradha Chougule</name><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author><author><name sortKey="Rekhi, Bharat" sort="Rekhi, Bharat" uniqKey="Rekhi B" first="Bharat" last="Rekhi">Bharat Rekhi</name><affiliation wicri:level="1"><nlm:aff id="af0030">Department of Pathology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Pathology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author><author><name sortKey="Ghosh, Jaya" sort="Ghosh, Jaya" uniqKey="Ghosh J" first="Jaya" last="Ghosh">Jaya Ghosh</name><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author><author><name sortKey="Philip, Deepa S J" sort="Philip, Deepa S J" uniqKey="Philip D" first="Deepa S. J." last="Philip">Deepa S. J. Philip</name><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author><author><name sortKey="Meurer, Marie" sort="Meurer, Marie" uniqKey="Meurer M" first="Marie" last="Meurer">Marie Meurer</name><affiliation wicri:level="1"><nlm:aff id="af0005">INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0035">Service d'Oncologie Médicale, AP-HM, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Service d'Oncologie Médicale, AP-HM, Marseille</wicri:regionArea></affiliation></author><author><name sortKey="Mackenzie, Karen L" sort="Mackenzie, Karen L" uniqKey="Mackenzie K" first="Karen L." last="Mackenzie">Karen L. Mackenzie</name><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation></author><author><name sortKey="Kavallaris, Maria" sort="Kavallaris, Maria" uniqKey="Kavallaris M" first="Maria" last="Kavallaris">Maria Kavallaris</name><affiliation wicri:level="1"><nlm:aff id="af0015">Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0040">Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney</wicri:regionArea></affiliation></author><author><name sortKey="Banavali, Shripad D" sort="Banavali, Shripad D" uniqKey="Banavali S" first="Shripad D." last="Banavali">Shripad D. Banavali</name><affiliation wicri:level="1"><nlm:aff id="af0010">Metronomics Global Health Initiative, Marseille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Metronomics Global Health Initiative, Marseille</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Medical Oncology, Tata Memorial Centre, Mumbai</wicri:regionArea></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.</p></sec><sec><title>Methods</title><p><italic>In vitro</italic> experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12 months, followed by propranolol-containing maintenance therapy.</p></sec><sec><title>Findings</title><p>Gene expression analysis showed expression of <italic>ADRB1</italic> and <italic>ADRB2</italic> adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine <italic>in vitro</italic>, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m<sup>2</sup>) and methotrexate (35 mg/m<sup>2</sup>) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11 months (range 5–24) and 16 months (range 10–30), respectively.</p></sec><sec><title>Interpretation</title><p>Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.</p></sec><sec><title>Funding</title><p>This study was funded by institutional and philanthropic grants.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Agulnik, M" uniqKey="Agulnik M">M. Agulnik</name></author><author><name sortKey="Yarber, J L" uniqKey="Yarber J">J.L. Yarber</name></author><author><name sortKey="Okuno, S H" uniqKey="Okuno S">S.H. Okuno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andre, N" uniqKey="Andre N">N. André</name></author><author><name sortKey="Banavali, S" uniqKey="Banavali S">S. Banavali</name></author><author><name sortKey="Snihur, Y" uniqKey="Snihur Y">Y. Snihur</name></author><author><name sortKey="Pasquier, E" uniqKey="Pasquier E">E. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">EBioMedicine</journal-id><journal-id journal-id-type="iso-abbrev">EBioMedicine</journal-id><journal-title-group><journal-title>EBioMedicine</journal-title></journal-title-group><issn pub-type="epub">2352-3964</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27211551</article-id><article-id pub-id-type="pmc">4856748</article-id><article-id pub-id-type="publisher-id">S2352-3964(16)30065-2</article-id><article-id pub-id-type="doi">10.1016/j.ebiom.2016.02.026</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject></subj-group></article-categories><title-group><article-title>Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pasquier</surname><given-names>Eddy</given-names></name><email>epasquier@ccia.unsw.edu.au</email><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0010" ref-type="aff">b</xref><xref rid="af0015" ref-type="aff">c</xref><xref rid="cr0005" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author"><name><surname>André</surname><given-names>Nicolas</given-names></name><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0010" ref-type="aff">b</xref><xref rid="af0020" ref-type="aff">d</xref></contrib><contrib contrib-type="author"><name><surname>Street</surname><given-names>Janine</given-names></name><xref rid="af0015" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Chougule</surname><given-names>Anuradha</given-names></name><xref rid="af0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Rekhi</surname><given-names>Bharat</given-names></name><xref rid="af0030" ref-type="aff">f</xref></contrib><contrib contrib-type="author"><name><surname>Ghosh</surname><given-names>Jaya</given-names></name><xref rid="af0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Philip</surname><given-names>Deepa S.J.</given-names></name><xref rid="af0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author"><name><surname>Meurer</surname><given-names>Marie</given-names></name><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0035" ref-type="aff">g</xref></contrib><contrib contrib-type="author"><name><surname>MacKenzie</surname><given-names>Karen L.</given-names></name><xref rid="af0015" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Kavallaris</surname><given-names>Maria</given-names></name><xref rid="af0015" ref-type="aff">c</xref><xref rid="af0040" ref-type="aff">h</xref></contrib><contrib contrib-type="author"><name><surname>Banavali</surname><given-names>Shripad D.</given-names></name><email>banavali_2000@yahoo.com</email><xref rid="af0010" ref-type="aff">b</xref><xref rid="af0025" ref-type="aff">e</xref><xref rid="cr0010" ref-type="corresp">⁎⁎</xref></contrib></contrib-group><aff id="af0005"><label>a</label>INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France</aff><aff id="af0010"><label>b</label>Metronomics Global Health Initiative, Marseille, France</aff><aff id="af0015"><label>c</label>Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia</aff><aff id="af0020"><label>d</label>Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille, France</aff><aff id="af0025"><label>e</label>Department of Medical Oncology, Tata Memorial Centre, Mumbai, India</aff><aff id="af0030"><label>f</label>Department of Pathology, Tata Memorial Centre, Mumbai, India</aff><aff id="af0035"><label>g</label>Service d'Oncologie Médicale, AP-HM, Marseille, France</aff><aff id="af0040"><label>h</label>Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia</aff><author-notes><corresp id="cr0005"><label>⁎</label>Correspondence to: E. Pasquier, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, High St, Randwick NSW 2031, Australia.Children's Cancer Institute Australia for Medical ResearchLowy Cancer Research CentreUNSW AustraliaPO Box 81High StRandwickNSW 2031Australia <email>epasquier@ccia.unsw.edu.au</email></corresp><corresp id="cr0010"><label>⁎⁎</label>Correspondence to: S. Banavali, Department of Medical and Pediatric Oncology, Tata Memorial Centre, Dr. Ernest Borges Road, Parel, Mumbai 400 012, India.Department of Medical and Pediatric OncologyTata Memorial CentreDr. Ernest Borges Road, ParelMumbai400 012India <email>banavali_2000@yahoo.com</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>17</day><month>2</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>4</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>17</day><month>2</month><year>2016</year></pub-date><volume>6</volume><fpage>87</fpage><lpage>95</lpage><history><date date-type="received"><day>15</day><month>1</month><year>2016</year></date><date date-type="rev-recd"><day>11</day><month>2</month><year>2016</year></date><date date-type="accepted"><day>15</day><month>2</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 The Authors</copyright-statement><copyright-year>2016</copyright-year></permissions><abstract><sec><title>Background</title><p>Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.</p></sec><sec><title>Methods</title><p><italic>In vitro</italic> experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12 months, followed by propranolol-containing maintenance therapy.</p></sec><sec><title>Findings</title><p>Gene expression analysis showed expression of <italic>ADRB1</italic> and <italic>ADRB2</italic> adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine <italic>in vitro</italic>, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m<sup>2</sup>) and methotrexate (35 mg/m<sup>2</sup>) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11 months (range 5–24) and 16 months (range 10–30), respectively.</p></sec><sec><title>Interpretation</title><p>Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.</p></sec><sec><title>Funding</title><p>This study was funded by institutional and philanthropic grants.</p></sec></abstract><abstract abstract-type="author-highlights"><title>Highlights</title><p><list list-type="simple"><list-item id="u0005"><label>•</label><p>A strong synergism was identified between propranolol and vinblastine in an <italic>in vitro</italic> model of angiosarcoma.</p></list-item><list-item id="u8805"><label>•</label><p>Adrenergic receptor expression was detected in angiosarcoma tumors providing a molecular target for propranolol.</p></list-item><list-item id="u0010"><label>•</label><p>Propranolol and vinblastine-based metronomic chemotherapy led to 100% response in 7 patients with inoperable angiosarcoma.</p></list-item><list-item id="u8445"><label>•</label><p>This treatment resulted in prolonged survival of angiosarcoma patients and warrants further investigation in larger trials.</p></list-item></list></p></abstract><kwd-group><title>Keywords</title><kwd>Angiosarcoma</kwd><kwd>Vascular tumor</kwd><kwd>Metronomic chemotherapy</kwd><kwd>Propranolol</kwd><kwd>Adrenergic receptor</kwd></kwd-group></article-meta></front><floats-group><fig id="f0005"><label>Fig. 1</label><caption><p>Expression of adrenergic receptor genes in immortalized and Ras-transformed vascular endothelial cells and <italic>in vitro</italic> sensitivity to propranolol. (A) Relative mRNA expression of <italic>ADRB1</italic> and <italic>ADRB2</italic> adrenergic receptor genes in immortalized (HMEC-1, BMhTERT-1 and BMST) and Ras-transformed (BMST-Ras) endothelial cell lines as determined by qRT-PCR using <italic>GAPDH</italic> as control gene. SK-N-MC neuroepithelioma cell line and HeLa cervical cancer cell line were included as positive controls for <italic>ADRB1</italic> and <italic>ADRB2</italic> expression, respectively. (B) Growth inhibition assay performed on BMST (<italic>black</italic>) and BMST-Ras (<italic>red</italic>) cell lines using Alamar Blue after 72 h incubation with propranolol. <italic>Points</italic>, % of cell proliferation as compared to untreated control cells, means of eight individual experiments; <italic>bars</italic>, 95% confidence interval; log scale for x axis.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="f0010"><label>Fig. 2</label><caption><p><italic>In vitro</italic> drug combination studies. Growth inhibition assays performed on BMST (<italic>left panel</italic>) and BMST-Ras (<italic>right panel</italic>) cell lines using Alamar Blue after 72 h incubation with doxorubicin (A), paclitaxel (B) and vinblastine (C) alone (<italic>black</italic> — <italic>solid line</italic>) or in combination with propranolol at 1 μM (<italic>black</italic> — <italic>broken line</italic>), 10 μM (<italic>green</italic> — <italic>solid line</italic>) and 50 μM (<italic>red</italic> — <italic>solid line</italic>). <italic>Points</italic>, % of cell proliferation as compared to untreated control cells, means of four individual experiments; <italic>bars</italic>, 95% confidence interval; log scale for x axis. Statistical analysis was performed by comparing the cytotoxic effect of chemotherapy alone and in combination with propranolol using Student's t test (*, p < 0.05; **, p < 0.01; ***, p < 0.001).</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="f0015"><label>Fig. 3</label><caption><p>Changes in sensitivity to chemotherapy. Histogram representation of the molar concentration of doxorubicin (A), paclitaxel (B) and vinblastine (C) required to inhibit 50% (IC<sub>50</sub>) of cell proliferation after 72 h drug incubation in absence (<italic>black</italic>) or presence of propranolol at 1 μM (<italic>hashed</italic>), 10 μM (<italic>green</italic>) and 50 μM (<italic>red</italic>). <italic>Columns</italic>, means of four individual experiments; <italic>bars</italic>, SEM. Statistical analysis was performed by comparing the IC<sub>50</sub> values of chemotherapy alone and in combination with propranolol using Student's t test (*, p < 0.05; **, p < 0.01; ***, p < 0.001).</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="f0020"><label>Fig. 4</label><caption><p>Combination indexes of propranolol with chemotherapy agents. Dot plot representation of the combination index of propranolol in association with doxorubicin, paclitaxel and vinblastine on BMST (□) and BMST-Ras (○) cell lines. Growth inhibition assays were performed using Alamar Blue after 72 h incubation with a range of chemotherapeutic drug concentrations in the presence or absence of propranolol at 50 μM. CI values were determined based on the Chou and Talalay method for all tested concentrations of chemotherapeutic drug. <italic>Bars</italic>, mean of at least three individual experiments; y axis, log scale.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="f0025"><label>Fig. 5</label><caption><p>Combination of propranolol and vinblastine in tumor spheroids. (A) Quantitative analysis of the growth of tumor spheroids formed by BMST-Ras cells on ultra-low attachment plates by daily volume measurements. Tumor spheroids were either untreated (<italic>black</italic>) or treated with 10 μM propranolol (<italic>green</italic>), 1 nM vinblastine (<italic>blue</italic>) or the combination (<italic>red</italic>). <italic>Points</italic>, means of at least three individual experiments; <italic>bars</italic>, SEM. Statistical analysis was performed by comparing the volume of tumor spheroids in absence and presence of treatment using Student's t test (*, p < 0.05; **, p < 0.01; ***, p < 0.001). (B) Representative photographs of BMST-Ras tumor spheroids after 120 h incubation with vinblastine and propranolol alone or in combination. Images were obtained using the 5 × objective of a Zeiss Axiovert 200 M. <italic>Inset</italic>, % of growth inhibition as compared to untreated tumor spheroids; <italic>scale bar</italic>, 200 μm. (C) Representative immunoblots of BMST-Ras tumor spheroid lysates after 120 h incubation with no drug (<italic>1</italic>), 10 μM propranolol (<italic>2</italic>), 1 nM vinblastine (<italic>3</italic>) or the combination (<italic>4</italic>). Membranes were probed with antibodies directed against cleaved PARP and GAPDH (loading control).</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="f0030"><label>Fig. 6</label><caption><p>Expression of β-adrenergic receptor gene in angiosarcoma tumors. <italic>ADRB1</italic> (<italic>top panel</italic> — 103 base pairs) and <italic>ADRB2</italic> (<italic>bottom panel</italic> — 138 base pairs) RT-PCR products analyzed by 2% agarose gel electrophoresis followed by ethidium bromide staining using 50 bp DNA marker. mRNA was isolated from tumor material obtained from patients #1, #3 and #4. Positive control RNA was extracted from HeLa (<italic>ADRB1</italic>) and SK-N-SH (<italic>ADRB2</italic>) cell lines.</p></caption><graphic xlink:href="gr6"></graphic></fig><fig id="f0035"><label>Fig. 7</label><caption><p>Clinical response of angiosarcoma patients. (A) Photographs of patient #2 who presented with a large angiosarcoma in the periorbital region and multiple lesions on the scalp. Sustained complete clinical response was observed in this patient. (B–C) PET and PET–CT scan images of patient #3 who presented with a primary angiosarcoma of the scalp and multiple metastases located in the vertebrae (arrows). Sustained complete clinical and metabolic response was observed in this patient.</p></caption><graphic xlink:href="gr7"></graphic></fig><table-wrap id="t0005" position="float"><label>Table 1</label><caption><p>Patient characteristics.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Patient no.</th><th align="left">Sex/<break></break>age</th><th align="left">New/<break></break>treated</th><th align="left">Sites involved</th><th align="left">Adverse prognostic factors</th><th align="left">Previous treatment</th><th align="left">Date Rx A started<xref rid="tf0005" ref-type="table-fn">⁎</xref></th></tr></thead><tbody><tr><td align="left">1</td><td align="left">F/53</td><td align="left">Treated</td><td align="left">(L) Breast primary. Orbit; bilateral breasts; cavernous sinus; ant. Chest wall; vertebrae</td><td align="left">Recurrent/metastatic; size > 5 cm; no surgery</td><td align="left">Surgery; weekly paclitaxel; thalidomide</td><td align="left">31/08/2011</td></tr><tr><td align="left">2</td><td align="left">M/72</td><td align="left">New</td><td align="left">Scalp primary. Multiple scalp lesions; large lesion on face</td><td align="left">Size > 5 cm; distant lesions; no surgery</td><td align="left">Nil</td><td align="left">01/03/2012</td></tr><tr><td align="left">3</td><td align="left">M/54</td><td align="left">New</td><td align="left">Scalp primary. Multiple scalp lesions; multiple vertebrae; mandible</td><td align="left">Metastatic; size > 5 cm; tumor necrosis; no surgery</td><td align="left">Nil</td><td align="left">05/09/2013</td></tr><tr><td align="left">4</td><td align="left">M/62</td><td align="left">New</td><td align="left">Para-vertebral masses primary. Multiple bones; bone-marrow; liver; spleen</td><td align="left">Metastatic; hepatic primary; poor performance status; no surgery</td><td align="left">Surgery (laminectomy)</td><td align="left">15/10/2013</td></tr><tr><td align="left">5</td><td align="left">M/35</td><td align="left">Treated</td><td align="left">(R) Hand primary; metastases to axilla; lung; pleural effusion</td><td align="left">Recurrent/metastatic; no surgery</td><td align="left">Surgery; doxorubicin & cisplatin chemotherapy; forequarter amputation<break></break>(R) UE + metastatectomy of lung nodules</td><td align="left">20/12/2013</td></tr><tr><td align="left">6</td><td align="left">F/49</td><td align="left">Treated</td><td align="left">Supra-orbital Primary; temple; above eyelids; post-auricular mass</td><td align="left">Recurrent/metastatic; no surgery</td><td align="left">Radiotherapy; cisplatin</td><td align="left">10/07/2014</td></tr><tr><td align="left">7</td><td align="left">M/20</td><td align="left">New</td><td align="left">Lung primary. Para tracheal nodes; liver; multiple bones; bone marrow</td><td align="left">Recurrent/metastatic; visceral; no surgery</td><td align="left">Nil</td><td align="left">03/11/2014</td></tr></tbody></table><table-wrap-foot><fn><p>Patients with skeletal involvement also received zoledronic acid.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tf0005"><label>⁎</label><p id="np0005">Rx A: Propranolol /Vinblastine/Methotrexate.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t0010" position="float"><label>Table 2</label><caption><p>Treatment duration and responses.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left">Patient no.</th><th align="left">Duration of Rx A<xref rid="tf0010" ref-type="table-fn">⁎</xref></th><th align="left">Best response to Rx A<xref rid="tf0010" ref-type="table-fn">⁎</xref></th><th align="left">Duration oral maintenance<xref rid="tf0015" ref-type="table-fn">⁎⁎</xref></th><th align="left">PFS</th><th align="left">Additional treatment</th><th align="left">Status as of Feb. 2016</th><th align="left">OS</th></tr></thead><tbody><tr><td align="left">1</td><td align="left">3 months (stopped on request)</td><td align="left">Very good partial response (VGPR)</td><td align="left">5 months</td><td align="left">7 months</td><td align="left">EBRT to eye; doxorubicin; gemcitabine + cisplatin</td><td align="left">Died of PD Oct. 2012</td><td align="left">14 months</td></tr><tr><td align="left">2</td><td align="left">12 months</td><td align="left">Complete clinical response. MRI still showed some diffuse scalp thickening: VGPR.</td><td align="left">12 months</td><td align="left">24 months</td><td align="left">EBRT to scalp</td><td align="left">Died of PD Oct. 2014</td><td align="left">30 months</td></tr><tr><td align="left">3</td><td align="left">12 months</td><td align="left">Complete clinical & metabolic response</td><td align="left">2 months</td><td align="left">14 months</td><td align="left">EBRT to scalp, bones; paclitaxel; thalidomide</td><td align="left">Died of PD Mar. 2015</td><td align="left">19 months</td></tr><tr><td align="left">4</td><td align="left">4 months (could not continue due to low platelet counts)</td><td align="left">Bone marrow complete morphological response</td><td align="left">Could not take much chemo due to autoimmune thrombo-cytopenia</td><td align="left">5 months</td><td align="left">EBRT to bones; thalidomide</td><td align="left">Died of PD Aug. 2014</td><td align="left">10 months</td></tr><tr><td align="left">5</td><td align="left">11 months</td><td align="left">Complete response of residual lung nodules</td><td align="left">3 months</td><td align="left">11 months</td><td align="left">Palliative care</td><td align="left">Died of progresive disease Apr. 2015</td><td align="left">16 months</td></tr><tr><td align="left">6</td><td align="left">12 months</td><td align="left">Very good partial response (VGPR)</td><td align="left">3 months</td><td align="left">19 + months</td><td align="left">N/A</td><td align="left">Alive on Rx <break></break>with VGPR</td><td align="left">19 + months</td></tr><tr><td align="left">7</td><td align="left">5 months (stopped due to logistics)</td><td align="left">Partial response</td><td align="left">Not started</td><td align="left">14 + months</td><td align="left">Presently on thalidomide/oral etoposide</td><td align="left">Alive on Rx with stable disease</td><td align="left">14 + months</td></tr></tbody></table><table-wrap-foot><fn><p>EBRT: external beam radio therapy; PD: progressive disease.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tf0010"><label>⁎</label><p id="np1010">Rx A: Propranolol /Vinblastine/Methotrexate.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tf0015"><label>⁎⁎</label><p id="np1510">Maintenance Rx: oral etoposide/cyclophosphamide/propranolol.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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