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Although developed to overcome resistance to conventional chemotherapy, metronomic chemotherapy is subject to resistance on its own. However, there is a paucity of information on mechanisms of resistance, on cross-resistance between metronomic regimens using different cytotoxic drugs, and on cross-resistance between metronomic versus conventional chemotherapy, or versus targeted antiangiogenic therapy. Herein we show that PC-3 human prostate cancer xenografts were sensitive to both metronomic cyclophosphamide and metronomic docetaxel, but resistant to metronomic topotecan. Conventional docetaxel was only moderately active in parental PC-3 and in metronomic cyclophosphamide resistant PC-3 tumors. However, in metronomic cyclophosphamide resistant PC-3 tumors combining conventional docetaxel or bolus cyclophosphamide therapy with continued metronomic cyclophosphamide was superior to each treatment alone. Furthermore, bevacizumab had single-agent activity against metronomic cyclophosphamide resistant PC-3 tumors. Microarray analyses identified altered regulation of protein translation as a potential mechanism of resistance to metronomic cyclophosphamide. Our results suggest that sensitivity to metronomic chemotherapy regimens using different cytotoxic drugs not only depends on shared mechanisms of action such as antiangiogenesis, but also on as yet unknown additional antitumor effects that appear to be drug-specific. As clinically observed with targeted antiangiogenic agents, the continued use of metronomic chemotherapy beyond progression may amplify the effects of added second-line therapies or vice versa. However, metronomic chemotherapy is no different from other systemic therapies in that predictive biomarkers will be essential to fully exploit this novel use of conventional chemotherapeutics.",{"EN":119},"Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy",{"VOID":121},"8910257164672836367",{"VOID":123},"10.1007\u002Fs10637-013-9974-3","PUBLICATION","VERIFIED","2024-04-29T10:40:04.217+00:00","Auto Verify","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-013-9974-3",[130,146,159,174,187,203],{"id":131,"sortIndex":21,"researcher":20,"roles":132,"affiliations":134,"properties":143},"e0ba28a5-d6a3-4950-8306-d2d273082595",[133],"AUTHOR",[135],{"id":136,"sortIndex":21,"affiliation":137,"properties":20},"55e6d992-e786-4a52-ab68-8474f7309668",{"id":136,"createTime":20,"updateTime":20,"relativeEntities":138,"slug":20,"properties":139,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":142,"statistic":20},[],{"title":140},{"VI":141},"Biological Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada",[],{"title":144},{"VI":145},"Annabelle Chow",{"id":147,"sortIndex":99,"researcher":20,"roles":148,"affiliations":149,"properties":156},"f9570fe2-9cbd-4489-9e8b-5b5aaa433cd2",[133],[150],{"id":136,"sortIndex":21,"affiliation":151,"properties":20},{"id":136,"createTime":20,"updateTime":20,"relativeEntities":152,"slug":20,"properties":153,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":155,"statistic":20},[],{"title":154},{"VI":141},[],{"title":157},{"VI":158},"Amy Wong",{"id":160,"sortIndex":100,"researcher":20,"roles":161,"affiliations":162,"properties":171},"920dfa13-7517-4ea6-9b05-8e3ede548f9d",[133],[163],{"id":164,"sortIndex":21,"affiliation":165,"properties":20},"86ba8a10-a1de-4348-9391-5c2332709ece",{"id":164,"createTime":20,"updateTime":20,"relativeEntities":166,"slug":20,"properties":167,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":170,"statistic":20},[],{"title":168},{"VI":169},"Biological Sciences, University of Texas El Paso, El Paso, USA",[],{"title":172},{"VI":173},"Giulio Francia",{"id":175,"sortIndex":101,"researcher":20,"roles":176,"affiliations":177,"properties":184},"30592464-6c63-4c68-8819-1d67cd5bf5b3",[133],[178],{"id":136,"sortIndex":21,"affiliation":179,"properties":20},{"id":136,"createTime":20,"updateTime":20,"relativeEntities":180,"slug":20,"properties":181,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":183,"statistic":20},[],{"title":182},{"VI":141},[],{"title":185},{"VI":186},"Shan Man",{"id":188,"sortIndex":189,"researcher":20,"roles":190,"affiliations":191,"properties":198},"80fe7312-ddd8-4df1-9bf0-fa84e1220022",4,[133],[192],{"id":136,"sortIndex":21,"affiliation":193,"properties":20},{"id":136,"createTime":20,"updateTime":20,"relativeEntities":194,"slug":20,"properties":195,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":197,"statistic":20},[],{"title":196},{"VI":141},[],{"title":199,"gsAuthor":201},{"VI":200},"Robert S. 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Cancer Treat Rev 37(6):444–455. doi:10.1016\u002Fj.ctrv.2010.12.006","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0305737210002173",{"doi":319},"10.1016\u002Fj.ctrv.2010.12.006",{"id":20,"text":321,"url":322,"identifiers":323},"Emmenegger U, Francia G, Shaked Y, Kerbel RS (2010) Metronomic chemotherapy: principles and lessons learned from applications in the treatment of metastatic prostate cancer. Recent Results Cancer Res 180:165–183. doi:10.1007\u002F978-3-540-78281-0_10","https:\u002F\u002Fdoi.org\u002F10.1007\u002F978-3-540-78281-0_10",{"mag":324,"openalex":325,"pm":326,"doi":327},"155649943","W155649943","20033383","10.1007\u002F978-3-540-78281-0_10",{"id":301,"text":329,"url":303,"identifiers":330},"Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350(17):1713–1721",{"doi":305},{"id":301,"text":332,"url":303,"identifiers":333},"Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 27(9):1368–1374",{"doi":305},{"id":301,"text":335,"url":303,"identifiers":336},"Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A (2006) Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. 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Drugs Aging 27(9):689–696. doi:10.2165\u002F11537480-000000000-00000",{"doi":348},"10.2165\u002F11537480-000000000-00000",{"id":20,"text":350,"url":20,"identifiers":351},"Fontana A, Bocci G, Galli L, D’Arcangelo M, Derosa L, Fioravanti A, Orlandi P, Barletta MT, Landi L, Bursi S, Minuti G, Bona E, Grazzini I, Danesi R, Falcone A (2010) Metronomic cyclophosphamide in elderly patients with advanced, castration-resistant prostate cancer. J Am Geriatr Soc 58(5):986–988. doi:10.1111\u002Fj.1532-5415.2010.02833.x",{"doi":352},"10.1111\u002Fj.1532-5415.2010.02833.x",{"id":354,"text":355,"url":356,"identifiers":357},"c81a066b-3e45-4d49-8cb9-bbdbe677f637","Kerbel RS (2012) Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer. Journal of Mammary Gland Biology and Neoplasia 17(3–4):229–239. doi:10.1007\u002Fs10911-012-9266-0","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10911-012-9266-0",{"doi":358},"10.1007\u002Fs10911-012-9266-0",{"id":301,"text":360,"url":303,"identifiers":361},"Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67(8):3560–3564",{"doi":305},{"id":363,"text":364,"url":365,"identifiers":366},"30ffd024-01e1-40bc-ac75-4def55c853ec","Martin-Padura I, Marighetti P, Agliano A, Colombo F, Larzabal L, Redrado M, Bleau AM, Prior C, Bertolini F, Calvo A (2012) Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts. Lab Invest 92(7):952–966. doi:10.1038\u002Flabinvest.2012.65","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0023683722013150",{"doi":367},"10.1038\u002Flabinvest.2012.65",{"id":301,"text":369,"url":303,"identifiers":370},"Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878–1886",{"doi":305},{"id":301,"text":372,"url":303,"identifiers":373},"Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S, Kerbel RS (2011) Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. Neoplasia 13(1):40–48",{"doi":305},{"id":20,"text":375,"url":376,"identifiers":377},"Thoenes L, Hoehn M, Kashirin R, Ogris M, Arnold GJ, Wagner E, Guenther M (2010) In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy. J Proteomics 73(7):1342–1354. doi:10.1016\u002Fj.jprot.2010.02.019","https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.jprot.2010.02.019",{"mag":378,"openalex":379,"pm":380,"doi":381},"2057308434","W2057308434","20219715","10.1016\u002Fj.jprot.2010.02.019",{"id":301,"text":383,"url":303,"identifiers":384},"Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS (2006) Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Cancer Res 66(3):1664–1674",{"doi":305},{"id":301,"text":386,"url":303,"identifiers":387},"Man S, Bocci G, Francia G, Green SK, Jothy S, Hanahan D, Bohlen P, Hicklin DJ, Bergers G, Kerbel RS (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62(10):2731–2735",{"doi":305},{"id":301,"text":389,"url":303,"identifiers":390},"Shaked Y, Emmenegger U, Francia G, Chen L, Lee CR, Man S, Paraghamian A, Ben-David Y, Kerbel RS (2005) Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res 65(16):7045–7051",{"doi":305},{"id":301,"text":392,"url":303,"identifiers":393},"Graham MA, Senan S, Robin H Jr, Eckhardt N, Lendrem D, Hincks J, Greenslade D, Rampling R, Kaye SB, von Roemeling R, Workman P (1997) Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial. Cancer Chemother Pharmacol 40(1):1–10",{"doi":305},{"id":20,"text":395,"url":396,"identifiers":397},"Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, Kerbel RS (2010) Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol Cancer Ther 9(4):996–1006. doi:10.1158\u002F1535-7163.MCT-09-0960","https:\u002F\u002Fdoi.org\u002F10.1158\u002F1535-7163.mct-09-0960",{"mag":398,"pmc":399,"openalex":400,"pm":401,"doi":402},"2137268781","2852477","W2137268781","20371722","10.1158\u002F1535-7163.mct-09-0960",{"id":301,"text":404,"url":303,"identifiers":405},"Gerber HP, Ferrara N (2005) Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 65(3):671–680",{"doi":305},{"id":407,"text":408,"url":409,"identifiers":410},"ea86d591-c43d-49e0-814e-68896fc58526","Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, Kerbel RS (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106(9):3058–3061. doi:10.1182\u002Fblood-2005-04-1422","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0006497120685500",{"doi":411},"10.1182\u002Fblood-2005-04-1422",{"id":20,"text":413,"url":414,"identifiers":415},"Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98(9):5116–5121. doi:10.1073\u002Fpnas.091062498","https:\u002F\u002Fdoi.org\u002F10.1073\u002Fpnas.091062498",{"openalex":416,"doi":417},"W4294107304","10.1073\u002Fpnas.091062498",{"id":20,"text":419,"url":420,"identifiers":421},"da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57. doi:10.1038\u002Fnprot.2008.211","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnprot.2008.211",{"mag":422,"openalex":423,"pm":424,"doi":425},"2158217645","W2158217645","19131956","10.1038\u002Fnprot.2008.211",{"id":20,"text":427,"url":428,"identifiers":429},"da Huang W, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37(1):1–13. doi:10.1093\u002Fnar\u002Fgkn923","https:\u002F\u002Fdoi.org\u002F10.1093\u002Fnar\u002Fgkn923",{"mag":430,"pmc":431,"openalex":432,"pm":433,"doi":434},"2133465414","2615629","W2133465414","19033363","10.1093\u002Fnar\u002Fgkn923",{"id":301,"text":436,"url":303,"identifiers":437},"Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512",{"doi":305},{"id":439,"text":440,"url":441,"identifiers":442},"79dc4409-de09-49b3-be80-becd5e06e90e","Sanborn SL, Cooney MM, Dowlati A, Brell JM, Krishnamurthi S, Gibbons J, Bokar JA, Nock C, Ness A, Remick SC (2008) Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles. Invest New Drugs 26(4):355–362. doi:10.1007\u002Fs10637-008-9137-0","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-008-9137-0",{"doi":443},"10.1007\u002Fs10637-008-9137-0",{"id":20,"text":445,"url":20,"identifiers":446},"Gorn M, Habermann CR, Anige M, Thom I, Schuch G, Andritzky B, Brandl S, Burkholder I, Edler L, Hossfeld DK, Bokemeyer C, Laack E (2008) A pilot study of docetaxel and trofosfamide as second-line ‘metronomic’ chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC). Onkologie 31(4):185–189. doi:10.1159\u002F000118626",{"doi":447},"10.1159\u002F000118626",{"id":20,"text":449,"url":450,"identifiers":451},"Young SD, Lafrenie RM, Clemons MJ (2012) Phase ii trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer. Curr Oncol 19(2):e75–e83. doi:10.3747\u002Fco.19.879","https:\u002F\u002Fdoi.org\u002F10.3747\u002Fco.19.879",{"mag":452,"pmc":453,"openalex":454,"pm":455,"doi":456},"1977284775","3320235","W1977284775","22514500","10.3747\u002Fco.19.879",{"id":20,"text":458,"url":459,"identifiers":460},"Facchini G, Caraglia M, Morabito A, Marra M, Piccirillo MC, Bochicchio AM, Striano S, Marra L, Nasti G, Ferrari E, Leopardo D, Vitale G, Gentilini D, Tortoriello A, Catalano A, Budillon A, Perrone F, Iaffaioli RV (2010) Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther 10(6):543–548. doi:10.4161\u002Fcbt.10.6.12611","https:\u002F\u002Fdoi.org\u002F10.4161\u002Fcbt.10.6.12611",{"mag":461,"openalex":462,"pm":463,"doi":464},"2053703910","W2053703910","20657175","10.4161\u002Fcbt.10.6.12611",{"id":301,"text":466,"url":303,"identifiers":467},"Ng SS, Sparreboom A, Shaked Y, Lee C, Man S, Desai N, Soon-Shiong P, Figg WD, Kerbel RS (2006) Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel. Clin Cancer Res 12(14 Pt 1):4331–4338",{"doi":305},{"id":20,"text":469,"url":470,"identifiers":471},"Wu H, Xin Y, Xiao Y, Zhao J (2012) Low-dose docetaxel combined with (−)-epigallocatechin-3-gallate inhibits angiogenesis and tumor growth in nude mice with gastric cancer xenografts. Cancer Biother Radiopharm 27(3):204–209. doi:10.1089\u002Fcbr.2011.1103","https:\u002F\u002Fdoi.org\u002F10.1089\u002Fcbr.2011.1103",{"mag":472,"openalex":473,"pm":474,"doi":475},"2080724955","W2080724955","22283637","10.1089\u002Fcbr.2011.1103",{"id":477,"text":478,"url":479,"identifiers":480},"e9242784-a903-419a-9d0b-1f3d1a21ed2c","Wu H, Xin Y, Zhao J, Sun D, Li W, Hu Y, Wang S (2011) Metronomic docetaxel chemotherapy inhibits angiogenesis and tumor growth in a gastric cancer model. Cancer Chemother Pharmacol 68(4):879–887. doi:10.1007\u002Fs00280-011-1563-6","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs00280-011-1563-6",{"doi":481},"10.1007\u002Fs00280-011-1563-6",{"id":301,"text":483,"url":303,"identifiers":484},"Kamat AA, Kim TJ, Landen CN Jr, Lu C, Han LY, Lin YG, Merritt WM, Thaker PH, Gershenson DM, Bischoff FZ, Heymach JV, Jaffe RB, Coleman RL, Sood AK (2007) Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res 67(1):281–288",{"doi":305},{"id":20,"text":486,"url":487,"identifiers":488},"Newman SP, Foster PA, Ho YT, Day JM, Raobaikady B, Kasprzyk PG, Leese MP, Potter BV, Reed MJ, Purohit A (2007) The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers. Br J Cancer 97(12):1673–1682. doi:10.1038\u002Fsj.bjc.6604100","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsj.bjc.6604100",{"mag":489,"pmc":490,"openalex":491,"pm":492,"doi":493},"1995667035","2360283","W1995667035","18026194","10.1038\u002Fsj.bjc.6604100",{"id":301,"text":495,"url":303,"identifiers":496},"Muramaki M, Miyake H, Hara I, Kamidono S (2005) Synergistic inhibition of tumor growth and metastasis by combined treatment with TNP-470 and docetaxel in a human prostate cancer PC-3 model. Int J Oncol 26(3):623–628",{"doi":305},{"id":20,"text":498,"url":499,"identifiers":500},"Hackl C, Man S, Francia G, Milsom C, Xu P, Kerbel RS (2012) Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. Gut. doi:10.1136\u002Fgutjnl-2011-301585","https:\u002F\u002Fdoi.org\u002F10.1136\u002Fgutjnl-2011-301585",{"mag":501,"pmc":502,"openalex":503,"pm":504,"doi":505},"2101928585","3553490","W2101928585","22543158","10.1136\u002Fgutjnl-2011-301585",{"id":301,"text":507,"url":303,"identifiers":508},"Merritt WM, Danes CG, Shahzad MM, Lin YG, Kamat AA, Han LY, Spannuth WA, Nick AM, Mangala LS, Stone RL, Kim HS, Gershenson DM, Jaffe RB, Coleman RL, Chandra J, Sood AK (2009) Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma. Cancer Biol Ther 8(16):1596–1603",{"doi":305},{"id":20,"text":510,"url":511,"identifiers":512},"Kumar S, Mokhtari RB, Sheikh R, Wu B, Zhang L, Xu P, Man S, Oliveira ID, Yeger H, Kerbel RS, Baruchel S (2011) Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res 17(17):5656–5667. doi:10.1158\u002F1078-0432.CCR-11-0078","https:\u002F\u002Fdoi.org\u002F10.1158\u002F1078-0432.ccr-11-0078",{"mag":513,"pmc":514,"openalex":515,"pm":516,"doi":517},"2156902079","3687796","W2156902079","21788355","10.1158\u002F1078-0432.ccr-11-0078",{"id":301,"text":519,"url":303,"identifiers":520},"du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab in human breast cancer xenografts. Clin Cancer Res 12(3 Pt 1):904–916",{"doi":305},{"id":20,"text":522,"url":523,"identifiers":524},"Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, Edwards J (2007) Expression levels of the JAK\u002FSTAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer 97(3):378–383. doi:10.1038\u002Fsj.bjc.6603871","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsj.bjc.6603871",{"mag":525,"pmc":526,"openalex":527,"pm":528,"doi":529},"1977818137","2360337","W1977818137","17595657","10.1038\u002Fsj.bjc.6603871",{"id":20,"text":531,"url":20,"identifiers":532},"Chang YM, Kung HJ, Evans CP (2007) Nonreceptor tyrosine kinases in prostate cancer. Neoplasia 9(2):90–100",{},{"id":20,"text":534,"url":535,"identifiers":536},"Paulo P, Barros-Silva JD, Ribeiro FR, Ramalho-Carvalho J, Jeronimo C, Henrique R, Lind GE, Skotheim RI, Lothe RA, Teixeira MR (2012) FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer. Genes Chromosomes Cancer 51(3):240–249. doi:10.1002\u002Fgcc.20948","https:\u002F\u002Fdoi.org\u002F10.1002\u002Fgcc.20948",{"mag":537,"openalex":538,"pm":539,"doi":540},"2115447984","W2115447984","22081504","10.1002\u002Fgcc.20948",{"id":20,"text":542,"url":543,"identifiers":544},"Erkizan HV, Uversky VN, Toretsky JA (2010) Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing’s sarcoma. Clin Cancer Res 16(16):4077–4083. doi:10.1158\u002F1078-0432.CCR-09-2261","http:\u002F\u002Fdx.doi.org\u002F10.1158\u002F1078-0432.ccr-09-2261",{"doi":545},"10.1158\u002F1078-0432.ccr-09-2261",{"id":20,"text":547,"url":548,"identifiers":549},"di Masi A, Gullotta F, Cappadonna V, Leboffe L, Ascenzi P (2011) Cancer predisposing mutations in BRCT domains. IUBMB life 63(7):503–512. doi:10.1002\u002Fiub.472","https:\u002F\u002Fdoi.org\u002F10.1002\u002Fiub.472",{"mag":550,"openalex":551,"pm":552,"doi":553},"2049963026","W2049963026","21698754","10.1002\u002Fiub.472",{"id":301,"text":555,"url":303,"identifiers":556},"Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100(22):12917–12922",{"doi":305},{"id":558,"text":559,"url":560,"identifiers":561},"b1e22cb5-3617-44aa-a429-8212df31d160","Jia L, Waxman DJ (2013) Thrombospondin-1 and pigment epithelium-derived factor enhance responsiveness of KM12 colon tumor to metronomic cyclophosphamide but have disparate effects on tumor metastasis. Cancer Lett 330(2):241–249. doi:10.1016\u002Fj.canlet.2012.11.055","https:\u002F\u002Fwww.sciencedirect.com\u002Fscience\u002Farticle\u002Fpii\u002FS0304383512007173",{"doi":562},"10.1016\u002Fj.canlet.2012.11.055",{"id":20,"text":564,"url":20,"identifiers":565},"Chabner BA, Roberts TG Jr (2005) Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 5(1):65–72. doi:10.1038\u002Fnrc1529",{"doi":566},"10.1038\u002Fnrc1529",{"id":20,"text":568,"url":569,"identifiers":570},"Raguz S, Yague E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99(3):387–391. doi:10.1038\u002Fsj.bjc.6604510","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fsj.bjc.6604510",{"mag":571,"pmc":572,"openalex":573,"pm":574,"doi":575},"2092677877","2527800","W2092677877","18665178","10.1038\u002Fsj.bjc.6604510",{"id":20,"text":577,"url":578,"identifiers":579},"Bock C, Lengauer T (2012) Managing drug resistance in cancer: lessons from HIV therapy. Nat Rev Cancer 12(7):494–501. doi:10.1038\u002Fnrc3297","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnrc3297",{"mag":580,"openalex":581,"pm":582,"doi":583},"2083339266","W2083339266","22673150","10.1038\u002Fnrc3297",{"id":301,"text":585,"url":303,"identifiers":586},"Aljuffali IA, Mock JN, Costyn LJ, Nguyen H, Nagy T, Cummings BS, Arnold RD (2011) Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer. Cancer Biol Ther 12(5):407–420",{"doi":305},{"id":20,"text":588,"url":589,"identifiers":590},"Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15(3):232–239. doi:10.1016\u002Fj.ccr.2009.01.021","https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ccr.2009.01.021",{"mag":591,"pmc":592,"openalex":593,"pm":594,"doi":595},"1967600348","4540346","W1967600348","19249681","10.1016\u002Fj.ccr.2009.01.021",{"id":301,"text":597,"url":303,"identifiers":598},"Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3):220–231",{"doi":305},{"id":20,"text":600,"url":601,"identifiers":602},"De Souza R, Zahedi P, Badame RM, Allen C, Piquette-Miller M (2011) Chemotherapy dosing schedule influences drug resistance development in ovarian cancer. Mol Cancer Ther 10(7):1289–1299. doi:10.1158\u002F1535-7163.MCT-11-0058","https:\u002F\u002Fdoi.org\u002F10.1158\u002F1535-7163.mct-11-0058",{"mag":603,"openalex":604,"pm":605,"doi":606},"2108052323","W2108052323","21551263","10.1158\u002F1535-7163.mct-11-0058",{"id":20,"text":608,"url":609,"identifiers":610},"De Souza R, Zahedi P, Moriyama EH, Allen CJ, Wilson BC, Piquette-Miller M (2010) Continuous docetaxel chemotherapy improves therapeutic efficacy in murine models of ovarian cancer. Mol Cancer Ther 9(6):1820–1830. doi:10.1158\u002F1535-7163.MCT-10-0249","https:\u002F\u002Fdoi.org\u002F10.1158\u002F1535-7163.mct-10-0249",{"mag":611,"openalex":612,"pm":613,"doi":614},"2138124620","W2138124620","20530719","10.1158\u002F1535-7163.mct-10-0249",{"id":301,"text":616,"url":303,"identifiers":617},"Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105(8):R15–R24",{"doi":305},{"id":301,"text":619,"url":303,"identifiers":620},"Ma L, Francia G, Viloria-Petit A, Hicklin DJ, du Manoir J, Rak J, Kerbel RS (2005) In vitro procoagulant activity induced in endothelial cells by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy. Cancer Res 65(12):5365–5373",{"doi":305},{"id":20,"text":622,"url":623,"identifiers":624},"Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. Jama 305(5):487–494. doi:10.1001\u002Fjama.2011.51","https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.yonc.2011.07.023",{"openalex":625,"doi":626},"W4239828555","10.1016\u002Fj.yonc.2011.07.023",{"id":20,"text":628,"url":629,"identifiers":630},"Ebos JM, Lee CR, Kerbel RS (2009) Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15(16):5020–5025. doi:10.1158\u002F1078-0432.CCR-09-0095","https:\u002F\u002Fdoi.org\u002F10.1158\u002F1078-0432.ccr-09-0095",{"mag":631,"pmc":632,"openalex":633,"pm":634,"doi":635},"2151637779","2743513","W2151637779","19671869","10.1158\u002F1078-0432.ccr-09-0095",{"id":20,"text":637,"url":638,"identifiers":639},"Verstovsek S (2013) Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgraduate medicine 125(1):128–135. doi:10.3810\u002Fpgm.2013.01.2628","https:\u002F\u002Fdoi.org\u002F10.3810\u002Fpgm.2013.01.2628",{"mag":640,"pmc":641,"openalex":642,"pm":643,"doi":644},"1980629288","5025038","W1980629288","23391678","10.3810\u002Fpgm.2013.01.2628",{"id":301,"text":646,"url":303,"identifiers":647},"Kubisch R, Meissner L, Krebs S, Blum H, Gunther M, Roidl A, Wagner E (2013) A comprehensive gene expression analysis of resistance formation upon metronomic cyclophosphamide therapy. Transl Oncol 6(1):1–9",{"doi":305},false,{"id":650,"createTime":651,"updateTime":652,"relativeEntities":653,"slug":654,"properties":655,"entityType":124,"verifyStatus":125,"verifyTime":666,"verifyNote":127,"languages":20,"translateLanguages":20,"viewCount":21,"primaryUrl":667,"fullTextUrl":20,"authors":668,"publicationType":233,"publisherRelationship":1006,"citationCount":20,"citationInfo":20,"publishDate":1062,"publishYear":1063,"citationAnalyzeStatus":1064,"lastCitationAnalyze":1065,"indexDatabases":1066,"openAccess":20,"references":20,"isForceReanalyzing":648},"a68e9659-7c4e-4d95-8172-c8f683a37992","2024-01-18T14:47:24.300+00:00","2026-08-16T01:40:37.121+00:00",[],"A-phase-Ib-study-of-GSK3052230-an-FGF-ligand-trap-in-combination-with-pemetrexed-and-cisplatin-in-patients-with-malignant-pleural-mesothelioma",{"abstract":656,"title":658,"gsPaper":660,"references":662,"doi":664},{"EN":657},"Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed\u002Fcisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg\u002Fkg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg\u002Fkg and one at 15 mg\u002Fkg. The MTD was defined as 15 mg\u002Fkg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1–56.5) (14\u002F36 PRs) and 47% had stable disease (17\u002F36), giving a disease control rate of 86%. At 15 mg\u002Fkg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4–65.1), and the median PFS was 7.4 months (95% CI: 6.7–13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg\u002Fkg weekly, GSK3052230 was well tolerated in combination with pemetrexed\u002Fcisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.",{"EN":659},"A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma",{"VOID":661},"[]",{"VOID":663},"Yap TA, Aerts JG, Popat S, Fennell DA (2017) Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer 17:475–488\nVogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of Pemetrexed in combination with Cisplatin versus Cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644\nBlackwell C, Sherk C, Fricko M, Ganji G, Barnette M, Hoang B, Tunstead J, Skedzielewski T, Alsaid H, Jucker BM, Minthorn E, Kumar R, DeYoung M (2016) Inhibition of FGF\u002FFGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039\u002FGSK3052230. Oncotarget 7:39861–39871\nStapelberg M, Gellert N, Swettenham E, Tomasetti M, Witting PK, Procopio A, Neuzil J (2005) α-Tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor Autocrine loop. J Biol Chem 280:25369–25376\nTurner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129\nGrose R, Dickson C (2005) Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 16:179–186\nItoh N (2007) The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull 30:1819–1825\nDieci MV, Arnedos M, Andre F, Soria JC (2013) Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov 3:264–279\nNishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T (2018) Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Investig New Drugs 36:424–434\nNogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J (2017) Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol 35:157–165\nMichael M, Bang Y-J, Park YS, Kang YK, Kim TM, Hamid O, Thornton D, Tate SC, Raddad E, Tie J (2017) A phase 1 study of LY2874455, an Oral selective pan-FGFR inhibitor, in patients with advanced Cancer. Target Oncol 12:463–474\nHarding TC, Long L, Palencia S, Zhang H, Sadra A, Hestir K et al (2013) Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of Cancer. Sci Transl Med 5:178ra39\nTolcher AW, Papadopoulos KP, Patnaik A, Wilson K, Thayer S, Zanghi J, Gemo AT, Kavanaugh WM, Keer HN, LoRusso PM (2016) A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors. Ann Oncol 27:526–532\nPattarozzi A, Carra E, Favoni RE, Würth R, Marubbi D, Filiberti RA, Mutti L, Florio T, Barbieri F, Daga A (2017) The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells. Stem Cell Res Ther 8:119\nSchelch K, Hoda MA, Klikovits T, Münzker J, Ghanim B, Wagner C, Garay T, Laszlo V, Setinek U, Dome B, Filipits M, Pirker C, Heffeter P, Selzer E, Tovari J, Torok S, Kenessey I, Holzmann K, Grasl-Kraupp B, Marian B, Klepetko W, Berger W, Hegedus B, Grusch M (2014) Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. Am J Respir Crit Care Med 190:763–772\nMarek LA, Hinz TK, von Massenhausen A, Olszewski KA, Kleczko EK, Boehm D et al (2014) Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma. Mol Cancer Res 12:1460–1469\nU.S. Department of Health and Human Services FaDA, Center for Drug Evaluation and Research (CDER) and Center for Veterinary Medicine (CVM) (2001) Guidance for Industry: Bioanalytical Method Validation\nDavidson B, Vintman L, Zcharia E, Bedrossian C, Berner A, Nielsen S, Ilan N, Vlodavsky I, Reich R (2004) Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma. Clin Exp Metastasis 21:469–476\nLi Q, Wang W, Yamada T, Matsumoto K, Sakai K, Bando Y, Uehara H, Nishioka Y, Sone S, Iwakiri S, Itoi K, Utsugi T, Yasumoto K, Yano S (2011) Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network. Am J Pathol 179:1483–1493\nKumar-Singh S, Weyler J, Martin MJ, Vermeulen PB, Van Marck E (1999) Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression. J Pathol 189:72–78\nHanigan MH, Devarajan P (2003) Cisplatin nephrotoxicity: molecular mechanisms. Cancer Ther 1:47–61\nZalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Rivière F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A (2016) Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma Avastin Cisplatin Pemetrexed study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387:1405–1414\nPaik PK, Shen R, Berger MF, Ferry D, Soria JC, Mathewson A, Rooney C, Smith NR, Cullberg M, Kilgour E, Landers D, Frewer P, Brooks N, André F (2017) A phase Ib open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers. Clin Cancer Res 23:5366–5373\nTabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC (2015) Phase I dose-escalation study of JNJ-42756493, an Oral Pan–fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. J Clin Oncol 33:3401–3408\nJavle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, el-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, van Cutsem E, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T (2018) Phase II study of BGJ398 in patients with FGFR-altered advanced Cholangiocarcinoma. J Clin Oncol 36:276–282\nGoyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, Lennerz JK, Vu P, Deshpande V, Kambadakone A, Mussolin B, Reyes S, Henderson L, Sun JE, van Seventer EE, Gurski JM Jr, Baltschukat S, Schacher-Engstler B, Barys L, Stamm C, Furet P, Ryan DP, Stone JR, Iafrate AJ, Getz G, Porta DG, Tiedt R, Bardelli A, Juric D, Corcoran RB, Bardeesy N, Zhu AX (2017) Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive Cholangiocarcinoma. Cancer Discov 7:252–263\nQuispel-Janssen JM, Badhai J, Schunselaar L, Price S, Brammeld J, Iorio F, Kolluri K, Garnett M, Berns A, Baas P, McDermott U, Neefjes J, Alifrangis C (2018) Comprehensive Pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition. Clin Cancer Res 24:84–94\nMarcq E, Siozopoulou V, De Waele J, van Audenaerde J, Zwaenepoel K, Santermans E et al (2017) Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology 6:e1261241\nAlley EW, Lopez J, Santoro A, Morosky A, Saraf S, Piperdi B, van Brummelen E (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18:623–630\nZalcman G, Mazieres J, Greillier L, Lantuejoul S, Dô P, Bylicki O et al (2017) LBA58_PR second or 3rd line Nivolumab (Nivo) versus Nivo plus Ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: up-dated results of the IFCT-1501 MAPS2 randomized phase 2 trial. 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Cancer 94:2584–2589. doi:10.1002\u002Fcncr.10526",{"doi":1322},"10.1002\u002Fcncr.10526",{"id":20,"text":1324,"url":20,"identifiers":1325},"Baselga J, Rosen N (2008) Determinants of RASistance to anti-epidermal growth factor receptor agents. J Clin Oncol 26:1582–1584. doi:10.1200\u002FJCO.2007.15.3700",{"doi":1326},"10.1200\u002FJCO.2007.15.3700",{"id":20,"text":1328,"url":20,"identifiers":1329},"Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF (2007) Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs 25:265–270. doi:10.1007\u002Fs10637-006-9020-9",{"doi":1330},"10.1007\u002Fs10637-006-9020-9",{"id":20,"text":1332,"url":20,"identifiers":1333},"Gordon MS, Matei D, Aghajanian C et al (2006) Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 24:4324–4332. doi:10.1200\u002FJCO.2005.05.4221",{"doi":1334},"10.1200\u002FJCO.2005.05.4221",{"id":20,"text":1336,"url":20,"identifiers":1337},"Kulke MH, Muzikansky A, Clark J et al (2006) A Phase II trial of vinorelbine in patients with advanced gastroesophageal adenocarcinoma. Cancer Invest 24:346–350. doi:10.1080\u002F07357900600705268",{"doi":1338},"10.1080\u002F07357900600705268",{"id":20,"text":1340,"url":20,"identifiers":1341},"Hussain MH, MacVicar GR, Petrylak DP et al (2007) Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2\u002Fneu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25:2218–2224. doi:10.1200\u002FJCO.2006.08.0994",{"doi":1342},"10.1200\u002FJCO.2006.08.0994",{"id":20,"text":1344,"url":20,"identifiers":1345},"Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634. doi:10.1200\u002FJCO.2007.14.7116",{"doi":1346},"10.1200\u002FJCO.2007.14.7116",{"id":20,"text":1348,"url":20,"identifiers":1349},"Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024. doi:10.1056\u002FNEJMoa051918",{"doi":1350},"10.1056\u002FNEJMoa051918",{"id":20,"text":1352,"url":20,"identifiers":1353},"Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G (2005) Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res 11:5223–5232. doi:10.1158\u002F1078-0432.CCR-05-0109",{"doi":1354},"10.1158\u002F1078-0432.CCR-05-0109",{"id":20,"text":1356,"url":20,"identifiers":1357},"Sevinc A, Turhal NS (2008) ‘Please, desist RECIST criteria in GIST, at least in me’. Onkologie 31:556. doi:10.1159\u002F000151688",{"doi":1358},"10.1159\u002F000151688",{"id":1360,"createTime":1361,"updateTime":1362,"relativeEntities":1363,"slug":1364,"properties":1365,"entityType":124,"verifyStatus":125,"verifyTime":1376,"verifyNote":127,"languages":20,"translateLanguages":20,"viewCount":21,"primaryUrl":1377,"fullTextUrl":20,"authors":1378,"publicationType":233,"publisherRelationship":1488,"citationCount":21,"citationInfo":1543,"publishDate":1546,"publishYear":1544,"citationAnalyzeStatus":1547,"lastCitationAnalyze":1362,"indexDatabases":1548,"openAccess":20,"references":20,"isForceReanalyzing":648},"1ac8205d-7ec8-45cb-8106-8fec6db3572b","2024-02-21T01:04:57.148+00:00","2026-07-29T02:07:25.559+00:00",[],"Improved-replication-efficiency-of-echovirus-5-after-transfection-of-colon-cancer-cells-using-an-authentic-5-RNA-genome-end-methodology",{"abstract":1366,"title":1368,"gsPaper":1370,"references":1372,"doi":1374},{"EN":1367},"Oncolytic virotherapy is a promising novel form of cancer treatment, but the therapeutic efficiency needs improvement. A potential strategy to enhance the therapeutic effect of oncolytic viruses is to use infectious nucleic acid as therapeutic agent to initiate an oncolytic infection, without administrating infectious viral particles. Here we demonstrate improved viral replication activation efficiency when transfecting cells with 5’ end authentic in vitro transcribed enterovirus RNA as compared to genomic RNA with additional non-genomic 5’ nucleotides generated by conventional cloning methods. We used echovirus 5 (E5) as an oncolytoc model virus due to its ability to replicate in and completely destroy five out of six colon cancer cell lines and kill artificial colon cancer tumors (HT29 spheroids), as shown here. An E5 infectious cDNA clone including a hammerhead ribozyme sequence was used to generate in vitro transcripts with native 5’ genome ends. In HT29 cells, activation of virus replication is approximately 20-fold more efficient for virus genome transcripts with native 5’ genome ends compared to E5 transcripts generated from a standard cDNA clone. This replication advantage remains when viral progeny release starts by cellular lysis 22 h post transfection. Hence, a native 5’ genomic end improves infection activation efficacy of infectious nucleic acid, potentially enhancing its therapeutic effect when used for cancer treatment. The clone design with a hammerhead ribozyme is likely to be applicable to a variety of oncolytic positive sense RNA viruses for the purpose of improving the efficacy of oncolytic virotherapy.",{"EN":1369},"Improved replication efficiency of echovirus 5 after transfection of colon cancer cells using an authentic 5’ RNA genome end methodology",{"VOID":1371},"[\"8807853197827777452\"]",{"VOID":1373},"Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. doi:10.3322\u002Fcaac.20107\nBourke MG, Salwa S, Harrington KJ, Kucharczyk MJ, Forde PF, de Kruijf M, Soden D, Tangney M, Collins JK, O’Sullivan GC (2011) The emerging role of viruses in the treatment of solid tumours. Cancer Treat Rev 37:618–632. doi:10.1016\u002Fj.ctrv.2010.12.003\nLiu TC, Galanis E, Kirn D (2007) Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol 4:101–117. doi:10.1038\u002Fncponc0736\nRussell SJ, Peng KW, Bell JC (2012) Oncolytic virotherapy. Nat Biotechnol 30:658–670. doi:10.1038\u002Fnbt.2287\nOchiai H, Campbell SA, Archer GE, Chewning TA, Dragunsky E, Ivanov A, Gromeier M, Sampson JH (2006) Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus. Clin Cancer Res 12:1349–1354. doi:10.1158\u002F1078-0432.CCR-05-1595\nReddy PS, Burroughs KD, Hales LM, Ganesh S, Jones BH, Idamakanti N, Hay C, Li SS, Skele KL, Vasko AJ, Yang J, Watkins DN, Rudin CM, Hallenbeck PL (2007) Seneca Valley virus, a systemically deliverable oncolytic picornavirus, and the treatment of neuroendocrine cancers. J Natl Cancer Inst 99:1623–1633\nRudin CM, Poirier JT, Senzer NN, Stephenson J Jr, Loesch D, Burroughs KD, Reddy PS, Hann CL, Hallenbeck PL (2011) Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin Cancer Res 17:888–895. doi:10.1158\u002F1078-0432.CCR-10-1706\nShafren DR, Au GG, Nguyen T, Newcombe NG, Haley ES, Beagley L, Johansson ES, Hersey P, Barry RD (2004) Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a21. Clin Cancer Res 10:53–60\nClinicalTrials.gov. References within. https:\u002F\u002Fclinicaltrials.gov\u002Fct2\u002Fhome. Accessed 23 May 2014\nDomingo E, Martin V, Perales C, Escarmis C (2008) Coxsackieviruses and quasispecies theory: evolution of enteroviruses. Curr Top Microbiol Immunol 323:3–32\nLauring AS, Andino R (2010) Quasispecies theory and the behavior of RNA viruses. PLoS Pathog 6:e1001005. doi:10.1371\u002Fjournal.ppat.1001005\nHolland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S (1982) Rapid evolution of RNA genomes. Science 215:1577–1585\nWorking PK, Lin A, Borellini F (2005) Meeting product development challenges in manufacturing clinical grade oncolytic adenoviruses. Oncogene 24:7792–7801. doi:10.1038\u002Fsj.onc.1209045\nRacaniello VR, Baltimore D (1981) Cloned poliovirus complementary DNA is infectious in mammalian cells. Science 214:916–919\nvan der Werf S, Bradley J, Wimmer E, Studier FW, Dunn JJ (1986) Synthesis of infectious poliovirus RNA by purified T7 RNA polymerase. Proc Natl Acad Sci U S A 83:2330–2334\nHadac EM, Kelly EJ, Russell SJ (2011) Myeloma xenograft destruction by a nonviral vector delivering oncolytic infectious nucleic acid. Mol Ther 19:1041–1047. doi:10.1038\u002Fmt.2011.68\nDuke GM, Palmenberg AC (1989) Cloning and synthesis of infectious cardiovirus RNAs containing short, discrete poly(C) tracts. J Virol 63:1822–1826\nKlump WM, Bergmann I, Muller BC, Ameis D, Kandolf R (1990) Complete nucleotide sequence of infectious Coxsackievirus B3 cDNA: two initial 5’ uridine residues are regained during plus-strand RNA synthesis. J Virol 64:1573–1583\nHerold J, Andino R (2000) Poliovirus requires a precise 5’ end for efficient positive-strand RNA synthesis. J Virol 74:6394–6400\nSilvestri LS, Parilla JM, Morasco BJ, Ogram SA, Flanegan JB (2006) Relationship between poliovirus negative-strand RNA synthesis and the length of the 3’ poly(A) tail. Virology 345:509–519. doi:10.1016\u002Fj.virol.2005.10.019\nLazouskaya NV, Palombo EA, Poh CL, Barton PA (2014) Construction of an infectious cDNA clone of Enterovirus 71: insights into the factors ensuring experimental success. J Virol Methods 197:67–76. doi:10.1016\u002Fj.jviromet.2013.12.005\nFriedrich J, Ebner R, Kunz-Schughart LA (2007) Experimental anti-tumor therapy in 3-D: spheroids-old hat or new challenge? Int J Radiat Biol 83:849–871. doi:10.1080\u002F09553000701727531\nIsraelsson S, Jonsson N, Gullberg M, Lindberg AM (2011) Cytolytic replication of echoviruses in colon cancer cell lines. Virol J 8:473. doi:10.1186\u002F1743-422X-8-473\nIsraelsson S, Gullberg M, Jonsson N, Roivainen M, Edman K, Lindberg AM (2010) Studies of Echovirus 5 interactions with the cell surface: heparan sulfate mediates attachment to the host cell. Virus Res 151:170–176. doi:10.1016\u002Fj.virusres.2010.05.001\nLindberg AM, Polacek C, Johansson S (1997) Amplification and cloning of complete enterovirus genomes by long distance PCR. J Virol Methods 65:191–199\nLindberg AM, Johansson S, Andersson A (1999) Echovirus 5: infectious transcripts and complete nucleotide sequence from uncloned cDNA. Virus Res 59:75–87\nLindberg AM, Andersson A (1999) Purification of full-length enterovirus cDNA by solid phase hybridization capture facilitates amplification of complete genomes. J Virol Methods 77:131–137\nHierholzer JC, Killington RA (1996) Virus isolation and quantitation. In: Mahy BWJ, Kangro HO (eds) Virology methods manual. Academic Pres Limited, Glasgow, pp 25–46\nJonsson N, Gullberg M, Lindberg AM (2009) Real-time polymerase chain reaction as a rapid and efficient alternative to estimation of picornavirus titers by tissue culture infectious dose 50 % or plaque forming units. Microbiol Immunol 53:149–154. doi:10.1111\u002Fj.1348-0421.2009.00107.x\nWillems E, Leyns L, Vandesompele J (2008) Standardization of real-time PCR gene expression data from independent biological replicates. Anal Biochem 379:127–129. doi:10.1016\u002Fj.ab.2008.04.036\nKhetsuriani N, Lamonte-Fowlkes A, Oberst S, Pallansch MA (2006) Enterovirus surveillance-United States, 1970–2005. MMWR Surveill Summ 55:1–20\nRoos FC, Roberts AM, Hwang II, Moriyama EH, Evans AJ, Sybingco S, Watson IR, Carneiro LA, Gedye C, Girardin SE, Ailles LE, Jewett MA, Milosevic M, Wilson BC, Bell JC, Der SD, Ohh M (2010) Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus. EMBO Mol Med 2:275–288. doi:10.1002\u002Femmm.201000081\nShafren DR, Sylvester D, Johansson ES, Campbell IG, Barry RD (2005) Oncolysis of human ovarian cancers by echovirus type 1. Int J Cancer 115:320–328\nAtkins GJ, Smyth JW, Fleeton MN, Galbraith SE, Sheahan BJ (2004) Alphaviruses and their derived vectors as anti-tumor agents. Curr Cancer Drug Targets 4:597–607\nPfeiffer JK, Kirkegaard K (2003) A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc Natl Acad Sci U S A 100:7289–7294. doi:10.1073\u002Fpnas.1232294100\nVignuzzi M, Wendt E, Andino R (2008) Engineering attenuated virus vaccines by controlling replication fidelity. Nat Med 14:154–161. doi:10.1038\u002Fnm1726",{"VOID":1375},"10.1007\u002Fs10637-014-0136-z","2024-05-16T12:24:33.861+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-014-0136-z",[1379,1403,1418,1440,1462,1475],{"id":1380,"sortIndex":21,"researcher":20,"roles":1381,"affiliations":1382,"properties":1400},"ff9b28ac-057c-4ac8-b70a-c850f6e1b889",[133],[1383,1391],{"id":1384,"sortIndex":21,"affiliation":1385,"properties":20},"2c9a94b6-8efd-47f7-a00e-face0185e975",{"id":1384,"createTime":20,"updateTime":20,"relativeEntities":1386,"slug":20,"properties":1387,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1390,"statistic":20},[],{"title":1388},{"VI":1389},"Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden",[],{"id":1392,"sortIndex":99,"affiliation":1393,"properties":1399},"a908c0f2-ef5f-493c-89d8-c6ba12fb4cfa",{"id":1392,"createTime":20,"updateTime":20,"relativeEntities":1394,"slug":20,"properties":1395,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1398,"statistic":20},[],{"title":1396},{"VI":1397},"Centre for Ecology and Evolution in Microbial Model Systems EEMiS, Linnaeus University, Kalmar, Sweden",[],{},{"title":1401},{"VI":1402},"S. Israelsson",{"id":1404,"sortIndex":99,"researcher":20,"roles":1405,"affiliations":1406,"properties":1413},"86c8d399-eeae-474c-b30c-a4a70e189091",[133],[1407],{"id":1384,"sortIndex":21,"affiliation":1408,"properties":20},{"id":1384,"createTime":20,"updateTime":20,"relativeEntities":1409,"slug":20,"properties":1410,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1412,"statistic":20},[],{"title":1411},{"VI":1389},[],{"title":1414,"gsAuthor":1416},{"VI":1415},"A. Sävneby",{"VOID":1417},"[\"YgjsgS4AAAAJ\"]",{"id":1419,"sortIndex":100,"researcher":20,"roles":1420,"affiliations":1421,"properties":1437},"5bb00048-9dcf-4904-a571-91d1fc453f03",[133],[1422,1428],{"id":1384,"sortIndex":21,"affiliation":1423,"properties":20},{"id":1384,"createTime":20,"updateTime":20,"relativeEntities":1424,"slug":20,"properties":1425,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1427,"statistic":20},[],{"title":1426},{"VI":1389},[],{"id":1429,"sortIndex":99,"affiliation":1430,"properties":1436},"18ea2111-17f4-435a-af67-21f8fa33d9dc",{"id":1429,"createTime":20,"updateTime":20,"relativeEntities":1431,"slug":20,"properties":1432,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1435,"statistic":20},[],{"title":1433},{"VI":1434},"Department of Molecular Biology, Umeå University, Umeå, Sweden",[],{},{"title":1438},{"VI":1439},"J-O. Ekström",{"id":1441,"sortIndex":101,"researcher":20,"roles":1442,"affiliations":1443,"properties":1459},"c1c902cc-8eba-4e1b-a6bc-8ac85bfa62b0",[133],[1444,1450],{"id":1384,"sortIndex":21,"affiliation":1445,"properties":20},{"id":1384,"createTime":20,"updateTime":20,"relativeEntities":1446,"slug":20,"properties":1447,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1449,"statistic":20},[],{"title":1448},{"VI":1389},[],{"id":1451,"sortIndex":99,"affiliation":1452,"properties":1458},"187af1b4-3406-4364-a825-9d611d8efb2f",{"id":1451,"createTime":20,"updateTime":20,"relativeEntities":1453,"slug":20,"properties":1454,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1457,"statistic":20},[],{"title":1455},{"VI":1456},"Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden",[],{},{"title":1460},{"VI":1461},"N. Jonsson",{"id":1463,"sortIndex":189,"researcher":20,"roles":1464,"affiliations":1465,"properties":1472},"e0088432-180f-4bae-a36a-f66aff13fe82",[133],[1466],{"id":1384,"sortIndex":21,"affiliation":1467,"properties":20},{"id":1384,"createTime":20,"updateTime":20,"relativeEntities":1468,"slug":20,"properties":1469,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1471,"statistic":20},[],{"title":1470},{"VI":1389},[],{"title":1473},{"VI":1474},"K. 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Ombrabulin was combined with two standard taxane\u002Fplatinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg\u002Fm2 with two chemotherapy doublets; OCD, 75 mg\u002Fm2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60\u002F75 mg\u002Fm2 docetaxel (D), day 2; and OCP, AUC5\u002F6 carboplatin (C) and paclitaxel (P) 175 mg\u002Fm2 (cohort 3) or 200 mg\u002Fm2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg\u002Fm2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3–4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin\u002Fdocetaxel or carboplatin\u002Fpaclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg\u002Fm2 ombrabulin with 75 mg\u002Fm2 cisplatin\u002F75 mg\u002Fm2 docetaxel or 200 mg\u002Fm2 paclitaxel\u002FAUC6 carboplatin, every 3 weeks.",{"EN":1559},"Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin\u002Fdocetaxel or carboplatin\u002Fpaclitaxel in patients with advanced solid tumors",{"VOID":1561},"[\"140255259804208543\"]",{"VOID":1563},"McKeage MJ, Baguley BC (2010) Disrupting established tumor blood vessels: an emerging therapeutic strategy for cancer. Cancer 116:1859–1871\nNihei Y, Suzuki M, Okano A, Tsuji T, Akiyama Y, Tsuruo T et al (1999) Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy. Jpn J Cancer Res 90:1387–1395\nHori K, Saito S, Kubota K (2002) A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs. Br J Cancer 86:1604–1614\nClemenson C, Jouannot E, Merino-Trigo A, Rubin-Carrez C, Deutsch E (2012) The vascular disrupting agent ombrabulin (AVE8062) enhances the efficacy of standard therapies in head and neck squamous cell carcinoma xenograft models. Invest New Drugs 31:273–284\nSessa C, Lorusso P, Tolcher A, Farace F, Lassau N, Delmonte A et al (2013) Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors. Clin Cancer Res 19:4832–4842\nSoria J, Sessa C, Perotti A, Massard C, Armand J, Lassaud N et al. (2008) A comprehensive study of translational research and safety exploration of the vascular disrupting agent (VDA) AVE8062 in combination with cisplatin administered every 3 weeks to patients with advanced solid tumors. Proceedings of the American Association for Cancer Research 99th Annual Meeting; Abstract LB-302.\nEskens F, Tresca P, Tosi D, Van Doorn L, Fontaine H, Van der Gaast A et al (2014) A phase I dose escalation and pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) combined with docetaxel in advanced solid tumors. Br J Cancer 110:2170–2177\nBruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB (1996) A population pharmacokinetic model for docetaxel (taxotere): model building and validation. J Pharmacokinet Biopharm 24:153–172\nBruno R, Hille D, Riva A, Vivier N, ten Bokkel Huinnink WW, van Oosterom AT et al (1998) Population pharmacokinetics\u002Fpharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196\nHarvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA et al (2006) Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 24:4963–4970\nSandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550\nLara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I et al (2011) Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol 29:2965–2971\nScagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F et al (2012) International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin\u002Fpaclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol 30:2829–2836\ndu Bois A, Huober J, Stopfer P, Pfisterer J, Wimberger P, Loibl S et al (2010) A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 21:370–375\nZweifel M, Jayson GC, Reed NS, Osborne R, Hassan B, Ledermann J et al (2011) Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. Ann Oncol 22:2036–2041\nSchiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98\nSubbiah IM, Lenihan DJ, Tsimberidou AM (2011) Cardiovascular toxicity profiles of vascular-disrupting agents. Oncologist 16:1120–1130\nFelici A, Loos WJ, Verweij J, Cirillo I, de Bruijn P, Nooter K et al (2006) A pharmacokinetic interaction study of docetaxel and cisplatin plus or minus 5-fluorouracil in the treatment of patients with recurrent or metastatic solid tumors. Cancer Chemother Pharmacol 58:673–680\nVergote I, Amant F, Oskay-Oezcelik G, Musib L, Michel AL, Darstein C et al (2009) Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study. Int J Gynecol Cancer 19:1505–1510\nOguri S, Sakakibara T, Mase H, Shimizu T, Ishikawa K, Kimura K et al (1988) Clinical pharmacokinetics of carboplatin. J Clin Pharmacol 28:208–215\nShea TC, Flaherty M, Elias A, Eder JP, Antman K, Begg C et al (1989) A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support. J Clin Oncol 7:651–661\nMorinaga Y, Suga Y, Ehara S, Harada K, Nihei Y, Suzuki M (2003) Combination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin against murine and human tumors in vivo. Cancer Sci 94:200–204\nRowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA et al (1991) Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 9:1692–1703\nMartinelli M, Bonezzi K, Riccardi E, Kuhn E, Frapolli R, Zucchetti M et al (2007) Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel. 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is a novel monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). This first-in-human, phase 1 dose-escalation study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of HLX22 in patients with advanced solid tumors who had failed or were intolerant to standard therapies. Enrolled patients aged 18 to 75 years with histologically confirmed HER2-overexpressing advanced or metastatic solid tumors received intravenous HLX22 once every 3 weeks at 3, 10, and 25 mg\u002Fkg. Primary endpoints were safety and the maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. Between July 31, 2019, and December 27, 2021, 11 patients were enrolled to receive HLX22 at 3 (n = 5), 10 (n = 3), and 25 (n = 3) mg\u002Fkg doses. The most common treatment-emergent adverse events were lymphocyte count decreased (45.5%), white blood cell count decreased (36.4%), and hypokalemia (36.4%). No serious adverse events or dose-limiting toxicities occurred during the treatment period, and the MTD was determined at 25 mg\u002Fkg once every 3 weeks. Systemic exposure of HLX22 increased with escalating dose levels. No patients achieved a complete or partial response, and four (36.4%) had stable disease. The disease control rate and median progression-free survival were 36.4% (95% confidence interval [CI], 7.9–64.8) and 44.0 days (95% CI, 41.0–170.0), respectively. HLX22 was well tolerated in patients with advanced solid tumors overexpressing HER2 after failure of standard therapies. The study results support further investigation of HLX22 in combination with trastuzumab and chemotherapy.",{"EN":1792},"HLX22, an anti-HER-2 monoclonal antibody, in patients with advanced solid tumors overexpressing human epidermal growth factor receptor 2: an open-label, dose-escalation, phase 1 trial",{"VOID":1794},"[\"15750337919434585147\"]",{"VOID":1796},"Hsu JL, Hung MC (2016) The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev 35(4):575–588. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs10555-016-9649-6\nYarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. https:\u002F\u002Fdoi.org\u002F10.1038\u002F35052073\nIqbal N, Iqbal N (2014) Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int 2014:852748. https:\u002F\u002Fdoi.org\u002F10.1155\u002F2014\u002F852748\nMenard S, Casalini P, Campiglio M, Pupa S, Agresti R, Tagliabue E (2001) HER2 overexpression in various tumor types, focussing on its relationship to the development of invasive breast cancer. Ann Oncol 12(Suppl 1):S15–19. https:\u002F\u002Fdoi.org\u002F10.1093\u002Fannonc\u002F12.suppl_1.s15\nOh DY, Bang YJ (2020) HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol 17(1):33–48. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41571-019-0268-3\nClifton GT, Peoples AGE (2021) Immunotherapy as a partner for HER2-directed therapies. Expert Rev Anticancer Ther 21(7):739–746. https:\u002F\u002Fdoi.org\u002F10.1080\u002F14737140.2021.1894932\nDawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH (2010) Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 28(1):92–98. https:\u002F\u002Fdoi.org\u002F10.1200\u002FJCO.2008.19.9844\nDerakhshani A, Rezaei Z, Safarpour H, Sabri M, Mir A, Sanati MA, Vahidian F, Gholamiyan Moghadam A, Aghadoukht A, Hajiasgharzadeh K, Baradaran B (2020) Overcoming trastuzumab resistance in HER2-positive breast cancer using combination therapy. J Cell Physiol 235(4):3142–3156. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjcp.29216\nVernieri C, Milano M, Brambilla M, Mennitto A, Maggi C, Cona MS, Prisciandaro M, Fabbroni C, Celio L, Mariani G, Bianchi GV, Capri G, de Braud F (2019) Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: current knowledge, new research directions and therapeutic perspectives. Crit Rev Oncol Hematol 139:53–66. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.critrevonc.2019.05.001\nCurigliano G, Mueller V, Borges V, Hamilton E, Hurvitz S, Loi S, Murthy R, Okines A, Paplomata E, Cameron D, Carey LA, Gelmon K, Hortobagyi GN, Krop I, Loibl S, Pegram M, Slamon D, Ramos J, Feng W, Winer E (2022) Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2 + metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol 33(3):321–329. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.annonc.2021.12.005\nSwain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J, Group CS (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724–734. https:\u002F\u002Fdoi.org\u002F10.1056\u002FNEJMoa1413513\nNational Comprehensive Cancer Network Guidelines in Oncology (NCCN Guidelines®), Breast Cancer, Version 2 (2022) (December 20, 2021). https:\u002F\u002Fwww.nccn.org\u002Fguidelines\u002Fguidelines-detail?category=1&id=1419. Accessed 06 May 2022\nUlrich L, Okines AFC (2021) Treating advanced unresectable or metastatic HER2-positive breast cancer: a spotlight on tucatinib. Breast Cancer 13:361–381. https:\u002F\u002Fdoi.org\u002F10.2147\u002FBCTT.S268451\nNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. United States Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2017) ; https:\u002F\u002Fctep.cancer.gov\u002Fprotocoldevelopment\u002Felectronic_applications\u002Fctc.htm. Accessed 13 May 2022\nEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejca.2008.10.026\nLencioni R, Llovet JM (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30(1):52–60. https:\u002F\u002Fdoi.org\u002F10.1055\u002Fs-0030-1247132\nSivagnanam K, Rahman ZU, Paul T (2016) Cardiomyopathy associated with targeted therapy for breast cancer. Am J Med Sci 351(2):194–199. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.amjms.2015.11.014\nHERCEPTIN® (trastuzumab) intravenous infusion [prescribing information] (2010). Genentech, Inc., South San Francisco, CA\nPERJETA® (pertuzumab) injection, for intravenous use [prescribing information]Genentech, Inc., South San Francisco, CA\nKADCYLA® (ado- (2019) Trastuzumab emtansine) for injection, for intravenous use [prescribing information]. Genentech, Inc., South San Francisco, CA\nENHERTU® (fam-trastuzumab (2021) deruxtecan-nxki) for injection, for intravenous use [prescribing information]. Daiichi Sankyo, Inc., Basking Ridge, NJ\nNg CM, Lum BL, Gimenez V, Kelsey S, Allison D (2006) Rationale for fixed dosing of pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 23(6):1275–1284. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs11095-006-0205-x\nQuartino AL, Li H, Kirschbrown WP, Mangat R, Wada DR, Garg A, Jin JY, Lum B (2019) Population pharmacokinetic and covariate analyses of intravenous trastuzumab (herceptin((R))), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors. Cancer Chemother Pharmacol 83(2):329–340. https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs00280-018-3728-z\nCarney WP, Bernhardt D, Jasani B (2013) Circulating HER2 extracellular domain: a specific and quantitative biomarker of prognostic value in all breast cancer patients? Biomark Cancer 5:31–39. https:\u002F\u002Fdoi.org\u002F10.4137\u002FBIC.S12389\nPetersen ER, Sorensen PD, Jakobsen EH, Madsen JS, Brandslund I (2013) Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer. Clin Chem Lab Med 51(7):1483–1492. https:\u002F\u002Fdoi.org\u002F10.1515\u002Fcclm-2012-0558\nZhang P, Xiao J, Ruan Y, Zhang Z, Zhang X (2020) Monitoring value of serum HER2 as a predictive biomarker in patients with metastatic breast cancer. Cancer Manag Res 12:4667–4675. https:\u002F\u002Fdoi.org\u002F10.2147\u002FCMAR.S254897\nLeyland-Jones B, Smith BR (2011) Serum HER2 testing in patients with HER2-positive breast cancer: the death knell tolls. Lancet Oncol 12(3):286–295. https:\u002F\u002Fdoi.org\u002F10.1016\u002FS1470-2045(10)70297-7\nMurthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Muller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP (2020) Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382(7):597–609. https:\u002F\u002Fdoi.org\u002F10.1056\u002FNEJMoa1914609\nWagner AD, Grabsch HI, Mauer M, Marreaud S, Caballero C, Thuss-Patience P, Mueller L, Elme A, Moehler MH, Martens U, Kang YK, Rha SY, Cats A, Tokunaga M, Lordick F (2019) EORTC-1203-GITCG - the “INNOVATION”-trial: effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer Group. BMC Cancer 19(1):494. https:\u002F\u002Fdoi.org\u002F10.1186\u002Fs12885-019-5675-4\nHofheinz RD, Haag GM, Ettrich TJ, Borchert K, Kretzschmar A, Teschendorf C, Margareta Siegler G, Ebert MP, Goekkurt E, Welslau M, Mahlberg O, Homann N, Pink D, Bechstein WO, Reichardt P, Gaiser T, Sookthai D, Pauligk C, Goetze TO, Al-Batran SE (2020) Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: final results of the PETRARCA multicenter randomized phase II trial of the AIO. J Clin Oncol 38:450\nChung HC, Bang YJ, C SF, Qin SK, Satoh T, Shitara K, Tabernero J, Van Cutsem E, Alsina M, Cao ZA, Lu J, Bhagia P, Shih CS, Janjigian YY (2021) First-line pembrolizumab\u002Fplacebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol 17(5):491–501. https:\u002F\u002Fdoi.org\u002F10.2217\u002Ffon-2020-0737",{"VOID":1798},"10.1007\u002Fs10637-023-01338-7","2024-05-28T00:55:01.198+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-023-01338-7",[1802,1817,1830,1845,1858,1871],{"id":1803,"sortIndex":21,"researcher":20,"roles":1804,"affiliations":1805,"properties":1814},"05c94a34-f720-4e57-bbb5-07522a2ecb91",[133],[1806],{"id":1807,"sortIndex":21,"affiliation":1808,"properties":20},"02bcd675-46c1-49c4-8824-6576a67959b0",{"id":1807,"createTime":20,"updateTime":20,"relativeEntities":1809,"slug":20,"properties":1810,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1813,"statistic":20},[],{"title":1811},{"VI":1812},"Phase I Clinical Trials Unit, The First Hospital of Jilin University, Changchun, China",[],{"title":1815},{"VI":1816},"Xiaoxue 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acid phenethyl ester (CAPE) is a phenolic compound initially identified in bee glue. CAPE is reported to exhibit antitumor activity in many cancer models. However, the effect of CAPE on multiple myeloma (MM) is not well studied. We investigated the anti-myeloma effect of CAPE, and the data showed that CAPE inhibited the growth of human MM cells in a dose (1 ~ 30 μM) and time (24 ~72 h) dependent manner without altering the viability of normal human peripheral blood B cells. Stress and toxicity pathway analysis demonstrated that CAPE, in a dose- and time-related fashion, induced the expression of apoptotic and oxidative stress-response genes including growth arrest and DNA-damage inducible, alpha and gamma (GADD45A and GADD45G) and heme oxygenase-1. Apoptosis of MM cells by CAPE was further confirmed through flow cytometric analysis with up to 50% apoptotic cells induced by 50 μM CAPE within 24 h. Western blot analysis revealed the CAPE-induced activation of apoptosis executioner enzyme caspase-3, and corresponding cleavage of its downstream target poly(ADP-ribose)polymerase (PARP). The oxidative stress caused by CAPE cytotoxicity in MM cells was evaluated through measurement of reactive oxygen species (ROS) level, antioxidant intervention and glutathione depletion. The intracellular ROS level was not elevated by CAPE, but the pretreatment of antioxidant (N-acetyl cysteine) and glutathione synthesis inhibitor (buthionine sulfoximine) suggested that CAPE may cause oxidative stress by decrease of intracellular antioxidant level rather than over production of ROS. These data suggest that CAPE promotes apoptosis through oxidative stress in human multiple myeloma cells.",{"EN":1956},"Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells",{"VOID":1958},"[\"12065726439359620684\"]",{"VOID":1960},"Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364(11):1046–1060. https:\u002F\u002Fdoi.org\u002F10.1056\u002FNEJMra1011442\nFairfax KA, Kallies A, Nutt SL, Tarlinton DM (2008) Plasma cell development: from B-cell subsets to long-term survival niches. Semin Immunol 20(1):49–58. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.smim.2007.12.002\nBakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80(9):2326–2335\nFonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H (2004) Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64(4):1546–1558\nChauhan D, Uchiyama H, Urashima M, Yamamoto K, Anderson KC (1995) Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells. Stem Cells 13(Suppl 2):35–39\nPodar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC (2001) Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 98(2):428–435\nMitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC (2006) The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42(11):1564–1573. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejca.2005.12.025\nHideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7(8):585–598. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnrc2189\nHazlehurst LA, Dalton WS (2001) Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev 20(1–2):43–50\nDalton WS (2003) The tumor microenvironment: focus on myeloma. Cancer Treat Rev 29(Suppl 1):11–19\nYounes H, Leleu X, Hatjiharissi E, Moreau AS, Hideshima T, Richardson P, Anderson KC, Ghobrial IM (2007) Targeting the phosphatidylinositol 3-kinase pathway in multiple myeloma. Clin Cancer Res 13(13):3771–3775. https:\u002F\u002Fdoi.org\u002F10.1158\u002F1078-0432.CCR-06-2921\nIshikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Otsuyama K, Zheng X, Kawano MM (2003) Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation. Leuk Lymphoma 44(9):1477–1481. https:\u002F\u002Fdoi.org\u002F10.3109\u002F10428190309178767\nLi ZW, Chen H, Campbell RA, Bonavida B, Berenson JR (2008) NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 15(4):391–399. https:\u002F\u002Fdoi.org\u002F10.1097\u002FMOH.0b013e328302c7f4\nHideshima T, Bergsagel PL, Kuehl WM, Anderson KC (2004) Advances in biology of multiple myeloma: clinical applications. Blood 104(3):607–618. https:\u002F\u002Fdoi.org\u002F10.1182\u002Fblood-2004-01-0037\nGentile M, Recchia AG, Mazzone C, Lucia E, Vigna E, Morabito F (2013) Perspectives in the treatment of multiple myeloma. Expert Opin Biol Ther 13(Suppl 1):S1–S22. https:\u002F\u002Fdoi.org\u002F10.1517\u002F14712598.2013.799132\nGullett NP, Ruhul Amin AR, Bayraktar S, Pezzuto JM, Shin DM, Khuri FR, Aggarwal BB, Surh YJ, Kucuk O (2010) Cancer prevention with natural compounds. Semin Oncol 37(3):258–281. https:\u002F\u002Fdoi.org\u002F10.1053\u002Fj.seminoncol.2010.06.014\nPatel S (2016) Emerging adjuvant therapy for Cancer: Propolis and its constituents. J Diet Suppl 13(3):245–268. https:\u002F\u002Fdoi.org\u002F10.3109\u002F19390211.2015.1008614\nSon S, Lewis BA (2002) Free radical scavenging and antioxidative activity of caffeic acid amide and ester analogues: structure-activity relationship. J Agric Food Chem 50(3):468–472\nToyoda T, Tsukamoto T, Takasu S, Shi L, Hirano N, Ban H, Kumagai T, Tatematsu M (2009) Anti-inflammatory effects of caffeic acid phenethyl ester (CAPE), a nuclear factor-kappaB inhibitor, on helicobacter pylori-induced gastritis in Mongolian gerbils. Int J Cancer 125(8):1786–1795. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fijc.24586\nTseng TH, Lee YJ (2006) Evaluation of natural and synthetic compounds from east Asiatic folk medicinal plants on the mediation of cancer. Anti Cancer Agents Med Chem 6(4):347–365\nNatarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci U S A 93(17):9090–9095\nReuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49(11):1603–1616. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.freeradbiomed.2010.09.006\nWu J, Omene C, Karkoszka J, Bosland M, Eckard J, Klein CB, Frenkel K (2011) Caffeic acid phenethyl ester (CAPE), derived from a honeybee product propolis, exhibits a diversity of anti-tumor effects in pre-clinical models of human breast cancer. Cancer Lett 308(1):43–53. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.canlet.2011.04.012\nLin HP, Jiang SS, Chuu CP (2012) Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction, and growth inhibition in PC-3 human prostate cancer cells. PLoS One 7(2):e31286. https:\u002F\u002Fdoi.org\u002F10.1371\u002Fjournal.pone.0031286\nAkyol S, Ozturk G, Ginis Z, Armutcu F, Yigitoglu MR, Akyol O (2013) In vivo and in vitro antineoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. Nutr Cancer 65(4):515–526. https:\u002F\u002Fdoi.org\u002F10.1080\u002F01635581.2013.776693\nWang X, Stavchansky S, Zhao B, Bynum JA, Kerwin SM, Bowman PD (2008) Cytoprotection of human endothelial cells from menadione cytotoxicity by caffeic acid phenethyl ester: the role of heme oxygenase-1. Eur J Pharmacol 591(1–3):28–35. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.ejphar.2008.06.017\nZaman S, Wang R, Gandhi V (2014) Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma 55(9):1980–1992. https:\u002F\u002Fdoi.org\u002F10.3109\u002F10428194.2013.855307\nWalker RE, Lawson MA, Buckle CH, Snowden JA, Chantry AD (2014) Myeloma bone disease: pathogenesis, current treatments and future targets. Br Med Bull 111(1):117–138. https:\u002F\u002Fdoi.org\u002F10.1093\u002Fbmb\u002Fldu016\nBynum JA, Wang X, Stavchansky SA, Bowman PD (2017) Time course expression analysis of 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole induction of Cytoprotection in human endothelial cells. Gene Regul Syst Bio 11: https:\u002F\u002Fdoi.org\u002F10.1177\u002F1177625017701106\nNicholson JK, Connelly J, Lindon JC, Holmes E (2002) Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Discov 1(2):153–161. https:\u002F\u002Fdoi.org\u002F10.1038\u002Fnrd728\nOrrenius S, Nicotera P, Zhivotovsky B (2011) Cell death mechanisms and their implications in toxicology. Toxicol Sci 119(1):3–19. https:\u002F\u002Fdoi.org\u002F10.1093\u002Ftoxsci\u002Fkfq268\nBeauregard AP, Harquail J, Lassalle-Claux G, Belbraouet M, Jean-Francois J, Touaibia M, Robichaud GA (2015) CAPE analogs induce growth arrest and apoptosis in breast Cancer cells. Molecules 20(7):12576–12589. https:\u002F\u002Fdoi.org\u002F10.3390\u002Fmolecules200712576\nOzturk G, Ginis Z, Akyol S, Erden G, Gurel A, Akyol O (2012) The anticancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci 16(15):2064–2068\nNowsheen S, Yang ES (2012) The intersection between DNA damage response and cell death pathways. Exp Oncol 34(3):243–254\nOzben T (2007) Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 96(9):2181–2196. https:\u002F\u002Fdoi.org\u002F10.1002\u002Fjps.20874\nKirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M, Du Z, Barsoum J, Bertin J (2008) Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther 7(8):2319–2327. https:\u002F\u002Fdoi.org\u002F10.1158\u002F1535-7163.MCT-08-0298\nLeon-Gonzalez AJ, Auger C, Schini-Kerth VB (2015) Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy. Biochem Pharmacol 98(3):371–380. https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.bcp.2015.07.017\nRahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, Dhama K (2014) Oxidative stress, prooxidants, and antioxidants: the interplay. Biomed Res Int 2014:761264–761219. https:\u002F\u002Fdoi.org\u002F10.1155\u002F2014\u002F761264",{"VOID":1962},"10.1007\u002Fs10637-018-0701-y","2024-05-08T08:12:11.069+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-018-0701-y",[1966,1981,1994,2007,2020,2033,2046],{"id":1967,"sortIndex":21,"researcher":20,"roles":1968,"affiliations":1969,"properties":1978},"5fbd1e8e-58e0-4a5a-a8b9-41e13fbfa7b6",[133],[1970],{"id":1971,"sortIndex":21,"affiliation":1972,"properties":20},"3c10c5ed-061c-4936-a8ea-761b9f3d5a76",{"id":1971,"createTime":20,"updateTime":20,"relativeEntities":1973,"slug":20,"properties":1974,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1977,"statistic":20},[],{"title":1975},{"VI":1976},"Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Suwanee, USA",[],{"title":1979},{"VI":1980},"Elizabeth Hernandez Marin",{"id":1982,"sortIndex":99,"researcher":20,"roles":1983,"affiliations":1984,"properties":1991},"00fbd6cc-80ee-422e-9cb8-458305d791a1",[133],[1985],{"id":1971,"sortIndex":21,"affiliation":1986,"properties":20},{"id":1971,"createTime":20,"updateTime":20,"relativeEntities":1987,"slug":20,"properties":1988,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":1990,"statistic":20},[],{"title":1989},{"VI":1976},[],{"title":1992},{"VI":1993},"Hana 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Ban",{"id":2021,"sortIndex":189,"researcher":20,"roles":2022,"affiliations":2023,"properties":2030},"c088c707-f118-4e1f-9ba9-0b59645061ce",[133],[2024],{"id":1971,"sortIndex":21,"affiliation":2025,"properties":20},{"id":1971,"createTime":20,"updateTime":20,"relativeEntities":2026,"slug":20,"properties":2027,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2029,"statistic":20},[],{"title":2028},{"VI":1976},[],{"title":2031},{"VI":2032},"Marie Katie Karaga",{"id":2034,"sortIndex":205,"researcher":20,"roles":2035,"affiliations":2036,"properties":2043},"58690eb9-235d-430f-ba80-490e17e8fac2",[133],[2037],{"id":1971,"sortIndex":21,"affiliation":2038,"properties":20},{"id":1971,"createTime":20,"updateTime":20,"relativeEntities":2039,"slug":20,"properties":2040,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2042,"statistic":20},[],{"title":2041},{"VI":1976},[],{"title":2044},{"VI":2045},"Rangaiah Shashidharamurthy",{"id":2047,"sortIndex":294,"researcher":20,"roles":2048,"affiliations":2049,"properties":2056},"9d4e4363-cdb5-4ada-a23a-178d6142b909",[133],[2050],{"id":1971,"sortIndex":21,"affiliation":2051,"properties":20},{"id":1971,"createTime":20,"updateTime":20,"relativeEntities":2052,"slug":20,"properties":2053,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2055,"statistic":20},[],{"title":2054},{"VI":1976},[],{"title":2057},{"VI":2058},"Xinyu Wang",{"url":1964,"publisher":2060,"properties":2110},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":2061,"slug":10,"properties":2062,"entityType":18,"verifyStatus":19,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":21,"subjectFields":2066,"manageAffiliations":2079,"indexDatabases":2090,"url":94,"thumbnailPath":20,"statistic":2105,"gsStatistic":20,"type":104,"analyzePriority":20},[],{"issn":2063,"title":2064,"eissn":2065},{"VOID":13},{"EN":15},{"VOID":17},[2067,2071,2075],{"id":24,"createTime":20,"updateTime":20,"relativeEntities":2068,"label":2069,"description":2070,"parentId":20,"standard":20,"scholarHubFieldId":20},[],{"EN":27},{},{"id":30,"createTime":20,"updateTime":20,"relativeEntities":2072,"label":2073,"description":2074,"parentId":20,"standard":20,"scholarHubFieldId":20},[],{"EN":33},{},{"id":36,"createTime":20,"updateTime":20,"relativeEntities":2076,"label":2077,"description":2078,"parentId":20,"standard":20,"scholarHubFieldId":20},[],{"EN":39},{},[2080,2085],{"id":43,"createTime":20,"updateTime":20,"relativeEntities":2081,"slug":20,"properties":2082,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2084,"statistic":20},[],{"title":2083},{"EN":47},[],{"id":50,"createTime":20,"updateTime":20,"relativeEntities":2086,"slug":20,"properties":2087,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2089,"statistic":20},[],{"title":2088},{"EN":54},[],[2091,2098],{"id":58,"indexDatabase":2092,"url":71,"indexYears":20,"academicFieldIds":2097,"indexDatabaseRanking":20},{"id":60,"createTime":20,"updateTime":20,"relativeEntities":2093,"label":2094,"description":2095,"key":67,"publicationTags":2096,"standard":20},[],{"EN":63,"VI":63},{"EN":65,"VI":66},[69,70],[73,74],{"id":76,"indexDatabase":2099,"url":87,"indexYears":88,"academicFieldIds":2104,"indexDatabaseRanking":93},{"id":78,"createTime":20,"updateTime":20,"relativeEntities":2100,"label":2101,"description":2102,"key":84,"publicationTags":2103,"standard":20},[],{"EN":81,"VI":81},{"EN":81,"VI":83},[86],[90,91,92],{"impactFactor":21,"impactFactorByYear":2106,"i10Index":21,"i10IndexLast5Year":21,"totalPublication":97,"totalPublicationByYear":2107,"totalCitation":21,"totalCitationByYear":2108,"totalCitationPerPublication":21,"totalCitationPerPublicationByYear":2109,"hindexLast5Year":21,"hindex":21},{},{"1986":99,"1991":99,"1992":99,"1996":99,"1997":99,"1998":99,"2003":99,"2005":100,"2006":99,"2007":100,"2008":101,"2009":101,"2010":99,"2011":99,"2012":99,"2013":100,"2017":99,"2018":99,"2019":99,"2020":99,"2021":99,"2022":99,"2023":100},{},{},{"pages":2111,"volume":2113},{"VOID":2112},"837-848",{"VOID":2114},"37",{"total":21,"publishYear":2116,"statisticByYear":2117},2018,{},"2018-11-22","2026-07-22T05:44:02.447+00:00",[69,93],{"id":2122,"createTime":2123,"updateTime":2124,"relativeEntities":2125,"slug":2126,"properties":2127,"entityType":124,"verifyStatus":125,"verifyTime":2138,"verifyNote":127,"languages":20,"translateLanguages":20,"viewCount":21,"primaryUrl":2139,"fullTextUrl":20,"authors":2140,"publicationType":233,"publisherRelationship":2298,"citationCount":2354,"citationInfo":2355,"publishDate":2356,"publishYear":1278,"citationAnalyzeStatus":19,"lastCitationAnalyze":2124,"indexDatabases":2357,"openAccess":20,"references":20,"isForceReanalyzing":648},"657d5007-6a4d-4f27-8122-27d80b1e4a14","2024-01-26T12:09:49.646+00:00","2026-07-21T07:50:01.166+00:00",[],"A-phase-II-multicenter-study-of-ipilimumab-with-or-without-dacarbazine-in-chemotherapy-na%C3%AFve-patients-with-advanced-melanoma",{"abstract":2128,"title":2130,"gsPaper":2132,"references":2134,"doi":2136},{"EN":2129},"Objective: Ipilimumab is a fully human, anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. Methods: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg\u002Fkg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg\u002Fm2\u002Fday. The primary efficacy endpoint was objective response rate. Results: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8–30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7–18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2–18.8) and 11.4 months (95% CI, 6.1–15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. Conclusion: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.",{"EN":2131},"A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma",{"VOID":2133},"[\"10811876406379085093\"]",{"VOID":2135},"Lens MB, Dawes M (2004) Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150:179–185\nCancer Facts & Figures (2009) American cancer society, Atlanta, GA, USA. http:\u002F\u002Fwww.cancer.org\u002Fdownloads\u002FSTT\u002F2009CAFFfinalsecured.pdf Accessed August 31st, 2009\nKorn EL, Liu PY, Lee SJ et al (2008) Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol 26:527–534\nBedikian AY, Millward M, Pehamberger H et al (2006) Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the oblimersen melanoma study group. J Clin Oncol 24:4738–4745\nAgarwala SS (2009) Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther 9:587–595\nPetrella T, Quirt I, Verma S, Haynes AE, Charette M, Bak K, Melanoma Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer Treat Rev 33:484–496\nPeggs KS, Segal NH, Allison JP (2007) Targeting immunosupportive cancer therapies: accentuate the positive, eliminate the negative. Cancer Cell 12:192–199\nMelero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L (2007) Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7:95–106\nMorse MA (2005) Technology evaluation: Ipilimumab, Medarex\u002FBristol-Myers Squibb. Curr Opin Mol Ther 7:588–597\nCranmer LD, Hersh E (2007) The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest 25:613–631\nFong L, Small EJ (2008) Anti–cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol 26:5275–5283\nRidolfi L, Ridolfi R (2009) Anti-CTLA-4 therapy in melanoma: role of ipilimumab (MDX-010). Expert Rev Dermatol 4:199–210\nHodi FS, Mihm MC, Soiffer RJ et al (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100:4712–4717\nLanger LF, Clay TM, Morse MA (2007) Update on anti-CTLA-4 antibodies in clinical trials. Expert Opin Biol Ther 7:1245–1256\nMargolin K (2008) Moving forward with immunotherapy: the rationale for anti-CTLA-4 therapy in melanoma. Comm Oncol 5:367–374\nO’Day SJ, Ibrahim R, DePril V et al (2008) Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies. J Clin Oncol 26(19s):abstract 9021\nWeber JS, O’Day S, Urba W et al (2008) Phase I\u002FII study of ipilimumab for patients with metastatic melanoma. J Clin Oncol 26:5950–5956\nPhan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377\nAttia P, Phan GQ, Maker AV et al (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053\nMaker AV, Phan GQ, Attia P et al (2005) Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I\u002FII study. Ann Surg Oncol 12:1005–1016\nWolchok JD, Neyns B, Linette G et al (2009) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol; in press\nUrba WJ, Weber JS, O’Day SJ et al (2008) Long-term survival of patients with advanced melanoma who received ipilimumab administered at 10mg\u002Fkg every 3weeks for 4 doses (induction dosing). J Clin Oncol 26(19s):abstract 3018\nTherasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216\nLake RA, Robinson BW (2005) Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 5:397–405\nZigler M, Villares GJ, Lev DC, Melnikova VO, Bar-Eli M (2008) Tumor immunotherapy in melanoma: strategies for overcoming mechanisms of resistance and escape. Am J Clin Dermatol 9:307–311\nRibas A, Camacho LH, Lopez Berestein G et al (2005) Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675, 206. J Clin Oncol 23:8968–8977\nWolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420\nWeber J (2009) Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother 58:823–830\nLin R, Yellin MJ, Lowy I, Safferman A, Chin K, Ibrahim R (2008) An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhea\u002Fcolitis: prevention of gastrointestinal perforation and\u002For colectomy. J Clin Oncol 26(19s):abstract 9063\nWeber J (2007) Review: Anti–CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12:864–872\nWeber J, Thompson JA, Hamid O et al (2009) A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591–5598\nClinicalTrials.gov. Dacarbazine and ipilimumab vs. dacarbazine with placebo in untreated, unresectable stage III or IV melanoma. www.clinicaltrials.gov\u002Fct\u002Fshow\u002FNCT00324155 Accessed September 3rd, 2009",{"VOID":2137},"10.1007\u002Fs10637-009-9376-8","2024-05-28T21:59:03.498+00:00","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.1007\u002Fs10637-009-9376-8",[2141,2156,2171,2188,2212,2227,2240,2255,2270,2283],{"id":2142,"sortIndex":21,"researcher":20,"roles":2143,"affiliations":2144,"properties":2153},"95714000-759c-40ba-a5d6-9d5b8f0feedd",[133],[2145],{"id":2146,"sortIndex":21,"affiliation":2147,"properties":20},"a95b3f39-cdb5-4e53-8d61-03b454ce4b0b",{"id":2146,"createTime":20,"updateTime":20,"relativeEntities":2148,"slug":20,"properties":2149,"entityType":20,"verifyStatus":20,"verifyTime":20,"verifyNote":20,"languages":20,"translateLanguages":20,"viewCount":20,"url":20,"parentIds":2152,"statistic":20},[],{"title":2150},{"VI":2151},"Arizona Cancer Center, University of Arizona, Tucson, USA",[],{"title":2154},{"VI":2155},"Evan M. 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The effects of furylquinones on cancer cells (Transplantable Liver Tumor, TLT) were assessed by measuring cell death (membrane cell lysis); intracellular contents of ATP and GSH and the activity of caspase-3 were used to determine the type of cell death. Most of the furylquinones tested (at a concentration of 25 μg\u002Fml) induced caspase-independent cell death but compound 4 had no cytotoxic effects. The levels of both ATP and GSH were severely affected by quinones 1, 2 and 5, while no effect was observed with compound 4. These cytotoxic properties of quinones are associated with physico-chemical properties as shown by the LUMO energies and lipophilicity. Interestingly, no cytotoxic effects of furylquinones were detected when the in vitro model of precision-cut liver slices (PCLS) was used. Indeed, although CYP2E1 activity was slightly affected, ATP and GSH levels as well as protein synthesis were not modified by furylquinones. Paracetamol, a well-known hepatotoxicant, reduced these parameters by more than 80% compared to control conditions. Taking into account the considerable incidence of adverse-effects induced by most current anticancer drugs, the selective cytotoxicity shown by compounds 1, 2 and 5, in particular that of 1, represents a safety factor that encourages the further development of these quinones as new drugs in cancer therapy.",{"EN":2368},"An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities",{"VOID":2370},"[\"7282784873114987883\"]",{"VOID":2372},"citation_journal_title=Ann Oncol; citation_title=Estimates of the cancer incidence and mortality in Europe in 2006; citation_author=J Ferlay, P Autier, M Boniol, M Heanue, M Colombet, P Boyle; citation_volume=18; citation_publication_date=2007; citation_pages=581-592; citation_doi=10.1093\u002Fannonc\u002Fmdl498; citation_id=CR1\ncitation_journal_title=CA Cancer J Clin; citation_title=Cancer statistics, 2009; citation_author=A Jemal, R Siegel, E Ward, Y Hao, J Xu, MJ Thun; citation_volume=59; citation_publication_date=2009; citation_pages=225-249; citation_doi=10.3322\u002Fcaac.20006; citation_id=CR2\ncitation_journal_title=Cell; citation_title=The hallmarks of cancer; citation_author=D Hanahan, RA Weinberg; citation_volume=100; citation_publication_date=2000; citation_pages=57-70; citation_doi=10.1016\u002FS0092-8674(00)81683-9; citation_id=CR3\ncitation_journal_title=Science; citation_title=On the origin of cancer cells; citation_author=OH Warburg; citation_volume=123; citation_publication_date=1956; citation_pages=309-314; citation_doi=10.1126\u002Fscience.123.3191.309; citation_id=CR4\ncitation_journal_title=Curr Med Chem; citation_title=In situ modulation of oxidative stress: a novel and efficient strategy to kill cancer cells; citation_author=J Verrax, R Curi, R Beck, N Dejeans, H Taper, P Buc Calderon; citation_volume=16; citation_publication_date=2009; citation_pages=1821-1830; citation_doi=10.2174\u002F092986709788186057; citation_id=CR5\ncitation_journal_title=Apoptosis; citation_title=Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death; citation_author=J Verrax, J Cadrobbi, C Marques, HS Taper, Y Habraken, J Piette, P Buc Calderon; citation_volume=9; citation_publication_date=2004; citation_pages=223-233; citation_doi=10.1023\u002FB:APPT.0000018804.26026.1a; citation_id=CR6\ncitation_journal_title=Eur J Cancer; citation_title=Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase; citation_author=FY Wu, TP Sun; citation_volume=35; citation_publication_date=1999; citation_pages=1388-1393; citation_doi=10.1016\u002FS0959-8049(99)00156-2; citation_id=CR7\ncitation_journal_title=Free Rad Biol Med; citation_title=Glial cell type-specific responses to menadione-induced oxidative stress; citation_author=SB Hollensworth, C Shen, JE Sim, DR Spitz, GL Wilson, SP Ledoux; citation_volume=28; citation_publication_date=2000; citation_pages=1161-1174; citation_doi=10.1016\u002FS0891-5849(00)00214-8; citation_id=CR8\ncitation_journal_title=Free Rad Biol Med; citation_title=Oxidative stress-induced apoptosis of endothelial cells; citation_author=MC Warren, EA Bump, D Medeiros, SJ Braunhut; citation_volume=29; citation_publication_date=2000; citation_pages=537-547; citation_doi=10.1016\u002FS0891-5849(00)00353-1; citation_id=CR9\ncitation_journal_title=Eur J Med Chem; citation_title=Part 1: Effect of vitamin C on the biological activity of two euryfurylbenzoquinones on TLT, a murine hepatoma cell line; citation_author=J Benites, L Rojo, JA Valderrama, H Taper, P Buc Calderon; citation_volume=43; citation_publication_date=2008; citation_pages=1813-1817; citation_doi=10.1016\u002Fj.ejmech.2007.11.015; citation_id=CR10\ncitation_journal_title=Chem Pharm Bull; citation_title=Part 2: influence of 2- euryfuryl-1, 4-naphthoquinone and its peri-hydroxy derivatives on both cell death and metabolism of TLT cells, a murine hepatoma cell line. Modulation of cytotoxicity by vitamin C; citation_author=J Benites, JA Valderrama, H Taper, P Buc Calderon; citation_volume=57; citation_publication_date=2009; citation_pages=615-619; citation_doi=10.1248\u002Fcpb.57.615; citation_id=CR11\ncitation_journal_title=Nucleic Acids Res; citation_title=Satellite DNA sequence content of polylysine-titratable and nuclease-resistant fractions of mouse liver hepatoma chromatin; citation_author=JD Duerksen, IJ Paul; citation_volume=3; citation_publication_date=1976; citation_pages=2277-2291; citation_id=CR12\ncitation_journal_title=Int J Cancer; citation_title=Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment; citation_author=HS Taper, J Gerlache, M Lans, M Roberfroid; citation_volume=40; citation_publication_date=1987; citation_pages=575-579; citation_doi=10.1002\u002Fijc.2910400424; citation_id=CR13\ncitation_journal_title=Cancer Res; citation_title=Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption; citation_author=BF Jordan, V Gregoire, RJ Demeure, P Sonveaux, O Feron, J O’Hara, V Vanhulle, N Delzenne, B Gallez; citation_volume=62; citation_publication_date=2002; citation_pages=3555-3561; citation_id=CR14\ncitation_journal_title=Toxicol In Vitro; citation_title=Role of ATP and glycogen reserves in both paracetamol sulfation and glucuronidation by cultured precision-cut rat liver slices; citation_author=E Evdokimova, H Taper, P Buc Calderon; citation_volume=15; citation_publication_date=2001; citation_pages=683-690; citation_doi=10.1016\u002FS0887-2333(01)00091-1; citation_id=CR15\ncitation_journal_title=Biochim Biophys Acta; citation_title=Reoxygenation after cold hypoxic storage of cultured precision-cut rat liver slices: effects on cellular metabolism and drug biotransformation; citation_author=E Rekka, E Evdokimova, S Eeckhoudt, P Buc Calderon; citation_volume=1568; citation_publication_date=2001; citation_pages=245-251; citation_id=CR16\ncitation_journal_title=Biochem Pharmacol; citation_title=Role of temperature on protein and mRNA cytochrome P450 3A (CYP3A) isozymes expression and midazolam oxidation by cultured rat precision-cut liver slices; citation_author=E Rekka, E Evdokimova, S Eeckhoudt, G Labbar, P Buc Calderon; citation_volume=64; citation_publication_date=2002; citation_pages=633-643; citation_doi=10.1016\u002FS0006-2952(02)01258-3; citation_id=CR17\ncitation_journal_title=Toxicol In Vitro; citation_title=The use of precision-cut liver slices from male Wistar rats as a tool to study age related changes in CYP3A induction and in formation of paracetamol conjugates; citation_author=V Wauthier, RK Verbeeck, P Buc Calderon; citation_volume=18; citation_publication_date=2004; citation_pages=879-885; citation_doi=10.1016\u002Fj.tiv.2004.04.013; citation_id=CR18\ncitation_journal_title=Mol Pharmacol; citation_title=Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine; citation_author=GB Corcoran, JR Mitchell, YN Vaishnav, EC Horning; citation_volume=18; citation_publication_date=1980; citation_pages=536-542; citation_id=CR19\ncitation_journal_title=Bioorg Med Chem; citation_title=Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines; citation_author=J Benites, JA Valderrama, F Rivera, L Rojo, N Campos, M Pedro, M Jose Nascimento; citation_volume=16; citation_publication_date=2008; citation_pages=862-868; citation_doi=10.1016\u002Fj.bmc.2007.10.028; citation_id=CR20\ncitation_journal_title=Proc Soc Exp Biol Med; citation_title=Lactic dehydrogenase activity in blood; citation_author=F Wroblewsky, JS Ladue; citation_volume=90; citation_publication_date=1955; citation_pages=210-213; citation_id=CR21\ncitation_journal_title=J Biol Chem; citation_title=Protein measurement with the Folin phenol reagent; citation_author=O Lowry, N Rosebrough, L Farr, R Randall; citation_volume=183; citation_publication_date=1951; citation_pages=265-275; citation_id=CR22\ncitation_journal_title=Anal Biochem; citation_title=A fluorometric assay for glutathione; citation_author=VH Cohn, JA Lyle; citation_volume=14; citation_publication_date=1966; citation_pages=434-440; citation_doi=10.1016\u002F0003-2697(66)90286-7; citation_id=CR23\ncitation_journal_title=Biochim Biophys Acta; citation_title=Incorporation of radioactive amino acids into protein in isolated rat hepatocytes; citation_author=PO Seglen; citation_volume=442; citation_publication_date=1976; citation_pages=391-404; citation_id=CR24\ncitation_journal_title=Life Sci; citation_title=Ageing is associated with increased expression but decreased activity of CYP2E1 in male Wistar rats; citation_author=V Wauthier, V Schenten, RK Verbeeck, P Buc Calderon; citation_volume=79; citation_publication_date=2006; citation_pages=1913-1920; citation_doi=10.1016\u002Fj.lfs.2006.06.046; citation_id=CR25\ncitation_title=Frontier orbitals and properties of organic molecules; citation_publication_date=1992; citation_id=CR26; citation_author=VF Traven; citation_publisher=Ellis Horwood Limited\ncitation_journal_title=J Biol Chem; citation_title=The BCR\u002FABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells; citation_author=M Sattler, S Verma, G Shrikhande, CH Byrne, YB Pride, T Winkler, EA Greenfield, R Salgia, JD Griffin; citation_volume=275; citation_publication_date=2000; citation_pages=24273-24278; citation_doi=10.1074\u002Fjbc.M002094200; citation_id=CR27\ncitation_journal_title=Mol Cell; citation_title=c- Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability; citation_author=O Vafa, M Wade, S Kern, M Beeche, TK Pandita, GM Hampton, GM Wahl; citation_volume=9; citation_publication_date=2002; citation_pages=1031-1044; citation_doi=10.1016\u002FS1097-2765(02)00520-8; citation_id=CR28\ncitation_journal_title=J Oral Pathol Med; citation_title=Antioxidant enzyme levels in oral squamous cell carcinoma and normal human oral epithelium; citation_author=J Yang, EW Lam, HM Hammad, TD Oberley, LW Oberley; citation_volume=31; citation_publication_date=2002; citation_pages=71-77; citation_doi=10.1034\u002Fj.1600-0714.2002.310202.x; citation_id=CR29\ncitation_journal_title=Cancer Cell; citation_title=Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate; citation_author=D Trachootham, Y Zhou, H Zhang, Y Demizu, Z Chen, H Pelicano, PJ Chiao, G Achanta, RB Arlinghaus, J Liu, P Huang; citation_volume=10; citation_publication_date=2006; citation_pages=241-252; citation_doi=10.1016\u002Fj.ccr.2006.08.009; citation_id=CR30\ncitation_journal_title=Cancer Res; citation_title=Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles; citation_author=T Watanabe, Y Komuro, T Kiyomatsu, T Kanazawa, Y Kazama, J Tanaka, T Tanaka, Y Yamamoto, M Shirane, T Muto, H Nagawa; citation_volume=66; citation_publication_date=2006; citation_pages=3370-3374; citation_doi=10.1158\u002F0008-5472.CAN-05-3834; citation_id=CR31\ncitation_journal_title=Int J Radiat Biol; citation_title=Role of pretherapeutic biomarkers in predicting postoperative radiotherapy response in patients with advanced squamous cell carcinoma; citation_author=RM Rawal, PS Patel, RK Vyas, RN Sainger, MH Shah, HM Peshavariya, DD Patel, JM Bhatavdekar; citation_volume=77; citation_publication_date=2001; citation_pages=1141-1146; citation_doi=10.1080\u002F09553000110067788; citation_id=CR32\ncitation_journal_title=Biochem Pharmacol; citation_title=Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1); citation_author=G Ekström, M Ingelman-Sundberg; citation_volume=38; citation_publication_date=1989; citation_pages=1313-1319; citation_doi=10.1016\u002F0006-2952(89)90338-9; citation_id=CR33\ncitation_journal_title=Arch Biochem Biophys; citation_title=NADPH-dependent microsomal electron transfer 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virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and overexpression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α are common in NPC. Anti-vascular agents have known clinical activity in patients with recurrent\u002F metastatic NPC and in this study, we investigated the anti-tumor effect of BI 836880, a humanized bispecific nanobody against VEGF and angiopoietin-2 (Ang2), in preclinical models of EBV-positive and EBV-negative NPC. The efficacy of BI 836880 was also compared with bevacizumab, a recombinant humanized monoclonal antibody against VEGF. We found that BI 836880 could exert growth-inhibitory effect on endothelial cells (HUVEC-C) and the EBV-negative NPC cell line (HK1), but to a lesser extent in the EBV-positive NPC cell lines, C17C and C666-1. In patients-derived xenograft (PDX) models of NPC - Xeno-2117 and Xeno-666, BI 836880 could suppress tumor growth and Ki67, as well as induce tumor necrosis and reduce microvessel density. Moreover, treatment with BI 836880 increased the level of macrophage infiltration in both PDX tumor models of NPC, suggesting that BI 836880 may exert immunomodulatory effect on the NPC immune microenvironment. When compared with bevacizumab, BI 836880 appeared to show at least comparable activity as bevacizumab in terms of its anti-proliferative and anti-angiogenic effects. This study showed that BI 836880 has anti-proliferative, anti-angiogenic and possibly immunomodulatory effect in clinical models of NPC, therefore the dual targeting of VEGF and Ang2 signaling in NPC should be further investigated.",{"EN":2541},"Preclinical evaluation of the VEGF\u002FAng2 bispecific nanobody BI 836880 in nasopharyngeal carcinoma models",{"VOID":2543},"[\"15057989791937423109\"]",{"VOID":2545},"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. Cancer J Clin 71(3):209–249\nWong KCW, Hui EP, Lo K-W, Lam WKJ, Johnson D, Li L et al (2021) Nasopharyngeal carcinoma: an evolving paradigm. Nat Reviews Clin Oncol 18(11):679–695\nDawson CW, Port RJ, Young LS (2012) The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Sem Cancer Biol 22(2):144–153\nChan SK, Chau SC, Chan SY, Tong CC, Lam KO, Lai-Wan Kwong D et al (2021) Incidence and demographics of nasopharyngeal carcinoma in Cheung Chau Island of Hong Kong-A distinct geographical area with minimal residential mobility and restricted Public Healthcare Referral Network. Cancer Control 28:10732748211047116\nPerri F, Della Vittoria Scarpati G, Caponigro F, Ionna F, Longo F, Buonopane S et al (2019) Management of recurrent nasopharyngeal carcinoma: current perspectives. Onco Targets Ther 12:1583–1591\nXue S, Song G, Zhu Y, Zhang N, Tan Y (2022) The efficacy and safety of VEGF\u002FVEGFR inhibitors in patients with recurrent or metastatic nasopharyngeal carcinoma: a meta-analysis. Oral Oncol 135:106231\nGoel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–882\nForsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613\nChen H-H, Weng B-Q, Cheng K-J, Liu H-Y, Wang S-Q, Lu Y-Y (2014) Effect of the vascular endothelial growth factor expression level on angiopoietin-2-mediated nasopharyngeal carcinoma growth. Vascular Cell 6(1):4\nPeng QX, Han YW, Zhang YL, Hu J, Fan J, Fu SZ et al (2017) Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma. Oncotarget 8(32):52813–52822\nKanthou C, Tozer G (2019) Targeting the vasculature of tumours: combining VEGF pathway inhibitors with radiotherapy. Br J Radiol 92(1093):20180405\nWu X, Giobbie-Hurder A, Liao X, Connelly C, Connolly EM, Li J et al (2017) Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy. Cancer Immunol Res 5(1):17–28\nYamazaki K, Koyama T, Shimizu T, Takahashi T, Watanabe J, Tanaka Y et al (2019) 74TiP - phase I study of BI 836880, a VEGF\u002FAng2-blocking nanobody®, as monotherapy and in combination with BI 754091, an anti-PD-1 antibody, in japanese patients (pts) with advanced solid tumours. Ann Oncol 30:ix28–ix9\nKovalchuk B, Berghoff AS, Karreman MA, Frey K, Piechutta M, Fischer M et al (2020) Nintedanib and a bi-specific anti-VEGF\u002FAng2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells. Clin Exp Metastasis 37(6):637–648\nHui EP, Chan AT, Pezzella F, Turley H, To KF, Poon TC et al (2002) Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 8(8):2595–2604\nHuang DP, Ho JH, Chan WK, Lau WH, Lui M (1989) Cytogenetics of undifferentiated nasopharyngeal carcinoma xenografts from southern chinese. Int J Cancer 43(5):936–939\nCheung ST, Huang DP, Hui AB, Lo KW, Ko CW, Tsang YS et al (1999) Nasopharyngeal carcinoma cell line (C666-1) consistently harbouring Epstein-Barr virus. Int J Cancer 83(1):121–126\nLo KW, Cheung ST, Leung SF, van Hasselt A, Tsang YS, Mak KF et al (1996) Hypermethylation of the p16 gene in nasopharyngeal carcinoma. Cancer Res 56(12):2721–2725\nMa BB, Lui VW, Hui CW, Lau CP, Wong CH, Hui EP et al (2014) Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models. Cancer Lett 343(1):24–32\nSerrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\u002FCDK4. Nature 366(6456):704–707\nAi L, Stephenson KK, Ling W, Zuo C, Mukunyadzi P, Suen JY et al (2003) The p16 (CDKN2a\u002FINK4a) tumor-suppressor gene in head and neck squamous cell carcinoma: a promoter methylation and protein expression study in 100 cases. Mod Pathol 16(9):944–950\nSiemerink MJ, Klaassen I, Vogels IM, Griffioen AW, Van Noorden CJ, Schlingemann RO (2012) CD34 marks angiogenic tip cells in human vascular endothelial cell cultures. Angiogenesis 15(1):151–163\nGerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715\nOzerdem U, Wojcik EM, Barkan GA, Duan X, Erşahin Ç (2013) A practical application of quantitative vascular image analysis in breast pathology. Pathol Res Pract 209(7):455–458\nKloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V et al (2016) Ang-2\u002FVEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 113(16):4476–4481\nZheng X, Turkowski K, Mora J, Brüne B, Seeger W, Weigert A et al (2017) Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget 8(29):48436–48452\nItaliani P, Boraschi D (2014) From monocytes to M1\u002FM2 macrophages: phenotypical vs. functional differentiation. Front Immunol 5:514\nCendrowicz E, Sas Z, Bremer E, Rygiel TP (2021) The role of Macrophages in Cancer Development and Therapy. Cancers (Basel) 13:8\nLu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C et al (2015) Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6(1):6676\nOrecchioni M, Ghosheh Y, Pramod AB, Ley K (2019) Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS–) vs. alternatively activated macrophages. Front Immunol 10\nTourneau CL, Claus R, Ricci F, Hackanson B, Rummelt C, Fietz O et al (2018) First-in-human phase I trial of BI 836880, a vascular endothelial growth factor (VEGF)\u002Fangiopoietin-2 (Ang-2)-blocking nanobody, given every 3 weeks (q3w) in patients (pts) with advanced\u002Fmetastatic solid tumors. J Clin Oncol 36(15suppl):12024\nMa W, Feng L, Zhang S, Zhang H, Zhang X, Qi X et al (2018) Induction of chemokine (C-C motif) ligand 5 by Epstein-Barr virus infection enhances tumor angiogenesis in nasopharyngeal carcinoma. Cancer Sci 109(5):1710–1722\nO’Neil JD, Owen TJ, Wood VHJ, Date KL, Valentine R, Chukwuma MB et al (2008) Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro. J Gen Virol 89(Pt 11):2833–2842\nHuang D, Song SJ, Wu ZZ, Wu W, Cui XY, Chen JN et al (2017) Epstein-Barr Virus-Induced VEGF and GM-CSF Drive Nasopharyngeal Carcinoma Metastasis via Recruitment and activation of macrophages. Cancer Res 77(13):3591–3604\nZhang J, Lu A, Li L, Yue J, Lu Y (2010) p16 modulates VEGF expression via its interaction with HIF-1alpha in breast cancer cells. Cancer Invest 28(6):588–597\nDe Palma M, Naldini L (2011) Angiopoietin-2 TIEs up macrophages in tumor angiogenesis. Clin Cancer Res 17(16):5226–5232\nGarcia-Bonilla L, Moore JM, Racchumi G, Zhou P, Butler JM, Iadecola C et al (2014) Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 193(5):2531–2537\nThwe PM, Amiel E (2018) The role of nitric oxide in metabolic regulation of dendritic cell immune function. 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