{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:44:55Z","timestamp":1790372695101,"version":"4.1.0"},"reference-count":51,"publisher":"Elsevier BV","issue":"1","license":[{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2014,5,5]],"date-time":"2014-05-05T00:00:00Z","timestamp":1399248000000},"content-version":"vor","delay-in-days":1220,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neoplasia"],"published-print":{"date-parts":[[2011,1]]},"DOI":"10.1593\/neo.101174","type":"journal-article","created":{"date-parts":[[2015,4,23]],"date-time":"2015-04-23T13:04:35Z","timestamp":1429794275000},"page":"40-48","source":"Crossref","is-referenced-by-count":58,"title":["Tumors That Acquire Resistance to Low-Dose Metronomic Cyclophosphamide Retain Sensitivity to Maximum Tolerated Dose Cyclophosphamide"],"prefix":"10.1016","volume":"13","author":[{"given":"Urban","family":"Emmenegger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Francia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Chow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuval","family":"Shaked","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Kouri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Man","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Kerbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1593\/neo.101174_bib1","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1056\/NEJMra0706596","article-title":"Tumor angiogenesis","volume":"358","author":"Kerbel","year":"2008","journal-title":"N Engl J Med"},{"key":"10.1593\/neo.101174_bib2","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nrclinonc.2009.130","article-title":"An overview of small-molecule inhibitors of VEGFR signaling","volume":"6","author":"Ivy","year":"2009","journal-title":"Nat Rev Clin Oncol"},{"key":"10.1593\/neo.101174_bib3","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrclinonc.2009.110","article-title":"Targeting angiogenesis: progress with anti VEGF treatment with large molecules","volume":"6","author":"Grothey","year":"2009","journal-title":"Nat Rev Clin Oncol"},{"key":"10.1593\/neo.101174_bib4","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrc2442","article-title":"Modes of resistance to anti-angiogenic therapy","volume":"8","author":"Bergers","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"10.1593\/neo.101174_bib5","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.1158\/1078-0432.CCR-09-0095","article-title":"Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy","volume":"15","author":"Ebos","year":"2009","journal-title":"Clin Cancer Res"},{"key":"10.1593\/neo.101174_bib6","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/nature04478","article-title":"Angiogenesis in life, disease and medicine","volume":"438","author":"Carmeliet","year":"2005","journal-title":"Nature"},{"key":"10.1593\/neo.101174_bib7","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.drup.2004.09.001","article-title":"Vascular remodeling and clinical resistance to antiangiogenic cancer therapy.","volume":"7","author":"Glade Bender","year":"2004","journal-title":"Drug Resist Updat"},{"key":"10.1593\/neo.101174_bib8","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/jmri.10181","article-title":"MRI of the tumor microenvironment","volume":"16","author":"Gillies","year":"2002","journal-title":"J Magn Reson Imaging"},{"key":"10.1593\/neo.101174_bib9","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1126\/science.1068327","article-title":"Effect of p53 status on tumor response to antiangiogenic therapy","volume":"295","author":"Yu","year":"2002","journal-title":"Science"},{"key":"10.1593\/neo.101174_bib10","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrc1369","article-title":"The anti-angiogenic basis of metronomic chemotherapy","volume":"4","author":"Kerbel","year":"2004","journal-title":"Nat Rev Cancer"},{"key":"10.1593\/neo.101174_bib11","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrclinonc.2010.82","article-title":"Metronomic chemotherapy: new rationale for new directions","volume":"7","author":"Pasquier","year":"2010","journal-title":"Nat Rev Clin Oncol"},{"key":"10.1593\/neo.101174_bib12","first-page":"1878","article-title":"Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug\u2013resistant cancer","volume":"60","author":"Browder","year":"2000","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib13","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1172\/JCI8829","article-title":"Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.","volume":"105","author":"Klement","year":"2000","journal-title":"J Clin Invest"},{"key":"10.1593\/neo.101174_bib14","first-page":"2731","article-title":"Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water","volume":"62","author":"Man","year":"2002","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib15","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1593\/neo.91872","article-title":"Impact of metronomic UFT\/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma","volume":"12","author":"Tang","year":"2010","journal-title":"Neoplasia"},{"key":"10.1593\/neo.101174_bib16","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1200\/JCO.2005.07.093","article-title":"A multitargeted, metronomic, and maximum-tolerated dose \u201cchemo-switch\u201d regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer","volume":"23","author":"Pietras","year":"2005","journal-title":"J Clin Oncol"},{"key":"10.1593\/neo.101174_bib17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12307-008-0012-5","article-title":"Systems biology: a therapeutic target for tumor therapy","volume":"1","author":"Reichle","year":"2008","journal-title":"Cancer Microenviron"},{"key":"10.1593\/neo.101174_bib18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-3-540-78281-0_10","article-title":"Metronomic chemotherapy: principles and lessons learned from applications in the treatment of metastatic prostate cancer","volume":"180","author":"Emmenegger","year":"2010","journal-title":"Recent Results Cancer Res"},{"key":"10.1593\/neo.101174_bib19","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S1470-2045(09)70383-3","article-title":"Activity of a multitargeted chemoswitch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06)","volume":"11","author":"Bellmunt","year":"2010","journal-title":"Lancet Oncol"},{"key":"10.1593\/neo.101174_bib20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jhep.2010.01.035","article-title":"Phase II study of combining sorafenib with metronomic tegafur\/ uracil for advanced hepatocellular carcinoma","volume":"53","author":"Hsu","year":"2010","journal-title":"J Hepatol"},{"key":"10.1593\/neo.101174_bib21","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa032792","article-title":"A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung","volume":"350","author":"Kato","year":"2004","journal-title":"N Engl J Med"},{"key":"10.1593\/neo.101174_bib22","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1200\/JCO.2008.18.3939","article-title":"Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as post-operative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial","volume":"27","author":"Watanabe","year":"2009","journal-title":"J Clin Oncol"},{"key":"10.1593\/neo.101174_bib23","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1186\/bcr1334","article-title":"Clinical trial update: International Breast Cancer Study Group","volume":"7","author":"Price","year":"2005","journal-title":"Breast Cancer Res"},{"issue":"suppl 5","key":"10.1593\/neo.101174_bib24","doi-asserted-by":"crossref","first-page":"v15","DOI":"10.1093\/annonc\/mdq160","article-title":"Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"21","author":"Cardoso","year":"2010","journal-title":"Ann Oncol"},{"key":"10.1593\/neo.101174_bib25","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.1158\/0008-5472.CAN-04-0580","article-title":"A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens","volume":"64","author":"Emmenegger","year":"2004","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib26","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1159\/000111479","article-title":"Five years of clinical experience with metronomic chemotherapy: achievements and perspectives","volume":"30","author":"Emmenegger","year":"2007","journal-title":"Onkologie"},{"key":"10.1593\/neo.101174_bib27","first-page":"221","article-title":"Differences in therapeutic indexes of combination metronomic chemotherapy and an anti\u2013VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts","volume":"8","author":"Klement","year":"2002","journal-title":"Clin Cancer Res"},{"key":"10.1593\/neo.101174_bib28","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1200\/JCO.2009.26.5520","article-title":"Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study","volume":"28","author":"Perry","year":"2010","journal-title":"J Clin Oncol"},{"key":"10.1593\/neo.101174_bib29","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/S0140-6736(09)60925-9","article-title":"Unravelling the mystery of the TACT trial","volume":"373","author":"Martin","year":"2009","journal-title":"Lancet"},{"key":"10.1593\/neo.101174_bib30","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1038\/sj.bjc.6604334","article-title":"Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes","volume":"98","author":"Calcagno","year":"2008","journal-title":"Br J Cancer"},{"key":"10.1593\/neo.101174_bib31","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1158\/0008-5472.CAN-05-2598","article-title":"Low-dose metronomic daily cyclophosphamide and weekly tirapazamine: a well-tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia","volume":"66","author":"Emmenegger","year":"2006","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib32","doi-asserted-by":"crossref","first-page":"6358","DOI":"10.1158\/1078-0432.CCR-09-0931","article-title":"Comparative impact of trastuzumab and cyclophosphamide on HER-2\u2013positive human breast cancer xenografts","volume":"15","author":"Francia","year":"2009","journal-title":"Clin Cancer Res"},{"key":"10.1593\/neo.101174_bib33","first-page":"6938","article-title":"Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs","volume":"62","author":"Bocci","year":"2002","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib34","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1158\/1535-7163.MCT-07-0181","article-title":"Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice","volume":"6","author":"Emmenegger","year":"2007","journal-title":"Mol Cancer Ther"},{"key":"10.1593\/neo.101174_bib35","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1042\/bj1730773","article-title":"Rapid purification and properties of potassium-activated aldehyde dehydrogenase from Saccharomyces cerevisiae","volume":"173","author":"Bostian","year":"1978","journal-title":"Biochem J"},{"key":"10.1593\/neo.101174_bib36","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.drup.2005.08.003","article-title":"Insights into oxaza-phosphorine resistance and possible approaches to its circumvention.","volume":"8","author":"Zhang","year":"2005","journal-title":"Drug Resist Updat"},{"key":"10.1593\/neo.101174_bib37","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1056\/NEJMoa040720","article-title":"Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer","volume":"351","author":"Tannock","year":"2004","journal-title":"N Engl J Med"},{"key":"10.1593\/neo.101174_bib38","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.ctrv.2008.05.004","article-title":"The role of doxorubicin and epirubicin in the treatment of patients with metastatic hormone-refractory prostate cancer","volume":"34","author":"Petrioli","year":"2008","journal-title":"Cancer Treat Rev"},{"key":"10.1593\/neo.101174_bib39","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1159\/000115967","article-title":"Resistance to chemotherapy in cancer: a complex and integrated cellular response","volume":"81","author":"Mellor","year":"2008","journal-title":"Pharmacology"},{"key":"10.1593\/neo.101174_bib40","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1200\/JCO.1997.15.1.368","article-title":"Fluorouracil in colorectal cancer\u2014a tale of two drugs: implications for biochemical modulation","volume":"15","author":"Sobrero","year":"1997","journal-title":"J Clin Oncol"},{"key":"10.1593\/neo.101174_bib41","doi-asserted-by":"crossref","first-page":"7045","DOI":"10.1158\/0008-5472.CAN-05-0765","article-title":"Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy","volume":"65","author":"Shaked","year":"2005","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib42","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1593\/neo.04757","article-title":"Continuous low-dose (met-ronomic) chemotherapy on rat prostate tumors evaluated using MRI in vivo and comparison with histology","volume":"7","author":"Zhao","year":"2005","journal-title":"Neoplasia"},{"key":"10.1593\/neo.101174_bib43","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/nrc2344","article-title":"Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability","volume":"8","author":"Bristow","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"10.1593\/neo.101174_bib44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/jcb.240560108","article-title":"Intrinsic or acquired drug resistance and metastasis: are they linked phenotypes?","volume":"56","author":"Kerbel","year":"1994","journal-title":"J Cell Biochem"},{"key":"10.1593\/neo.101174_bib45","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1126\/science.1127592","article-title":"Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors","volume":"313","author":"Shaked","year":"2006","journal-title":"Science"},{"key":"10.1593\/neo.101174_bib46","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1097\/01.cad.0000224454.46824.fc","article-title":"Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer","volume":"17","author":"Orlando","year":"2006","journal-title":"Anticancer Drugs"},{"key":"10.1593\/neo.101174_bib47","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1186\/1471-2407-9-347","article-title":"Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study","volume":"9","author":"Lievre","year":"2009","journal-title":"BMC Cancer"},{"key":"10.1593\/neo.101174_bib48","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/S0002-9440(10)64083-7","article-title":"Heterogeneous vascular dependence of tumor cell populations","volume":"158","author":"Yu","year":"2001","journal-title":"Am J Pathol"},{"key":"10.1593\/neo.101174_bib49","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s11060-008-9718-y","article-title":"Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan","volume":"91","author":"Zuniga","year":"2009","journal-title":"J Neurooncol"},{"key":"10.1593\/neo.101174_bib50","first-page":"1931","article-title":"What do oncogenic mutations have to do with angiogenesis\/vascular dependence of tumors?","volume":"62","author":"Rak","year":"2002","journal-title":"Cancer Res"},{"key":"10.1593\/neo.101174_bib51","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.jprot.2010.02.019","article-title":"In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy","volume":"73","author":"Thoenes","year":"2010","journal-title":"J Proteomics"}],"container-title":["Neoplasia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1476558611801107?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1476558611801107?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2018,9,23]],"date-time":"2018-09-23T07:29:13Z","timestamp":1537687753000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1476558611801107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,1]]}},"alternative-id":["S1476558611801107"],"URL":"https:\/\/doi.org\/10.1593\/neo.101174","relation":{},"ISSN":["1476-5586"],"issn-type":[{"value":"1476-5586","type":"print"}],"subject":[],"published":{"date-parts":[[2011,1]]}}}