Investigational New Drugs

, Volume 32, Issue 1, pp 47–59 | Cite as

Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy

  • Annabelle Chow
  • Amy Wong
  • Giulio Francia
  • Shan Man
  • Robert S. Kerbel
  • Urban EmmeneggerEmail author


Low-dose metronomic chemotherapy is an emerging form of chemotherapy with distinct mechanisms of action from conventional chemotherapy (e.g., antiangiogenesis). 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.


Low-dose metronomic chemotherapy Maximum tolerated dose chemotherapy Drug resistance Prostate cancer Cyclophosphamide Docetaxel 



These studies were conducted with the support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario as well as by a Prostate Cancer Canada Clinician-Scientist Award to U. Emmenegger, and by grants to Robert S. Kerbel from the Canadian Institutes for Health Research (CIHR) and the National Institutes of Health (CA-41233), USA. Robert S. Kerbel is a Tier I Canada Research Chair in Tumor Biology, Angiogenesis, and Antiangiogenic Therapy. G. Francia was in part supported by University of Texas at El Paso URI and IDR2 grants. We thank Cynthia M. Rodriguez and Karla Parra for their help with the preparation of this manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10637_2013_9974_MOESM1_ESM.doc (41 kb)
Supplementary Table 1 One-Class SAM Analysis (all genes) (DOC 41 kb)
10637_2013_9974_MOESM2_ESM.doc (74 kb)
Supplementary Table 2 SAM Analysis (genes with absolute values of log2 ratio ≥ 1 in at least one observation) (DOC 74 kb)


  1. 1.
    Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4(6):423–436CrossRefPubMedGoogle Scholar
  2. 2.
    Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7(8):455–465. doi: 10.1038/nrclinonc.2010.82 CrossRefPubMedGoogle Scholar
  3. 3.
    Nelius T, Rinard K, Filleur S (2011) Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature. Cancer Treat Rev 37(6):444–455. doi: 10.1016/j.ctrv.2010.12.006 CrossRefPubMedGoogle Scholar
  4. 4.
    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: 10.1007/978-3-540-78281-0_10 CrossRefPubMedGoogle Scholar
  5. 5.
    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):1713–1721CrossRefPubMedGoogle Scholar
  6. 6.
    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):1368–1374CrossRefPubMedGoogle Scholar
  7. 7.
    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. J Clin Oncol 24(22):3623–3628CrossRefPubMedGoogle Scholar
  8. 8.
    Borne E, Desmedt E, Duhamel A, Mirabel X, Dziwniel V, Maire C, Florin V, Martinot V, Penel N, Vercambre-Darras S, Mortier L (2009) Oral metronomic cyclophosphamide in elderly with metastatic melanoma. Invest New Drugs. doi: 10.1007/s10637-009-9298-5 PubMedGoogle Scholar
  9. 9.
    Fontana A, Falcone A, Derosa L, Di Desidero T, Danesi R, Bocci G (2010) Metronomic chemotherapy for metastatic prostate cancer: a ‘young’ concept for old patients? Drugs Aging 27(9):689–696. doi: 10.2165/11537480-000000000-00000 CrossRefPubMedGoogle Scholar
  10. 10.
    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/j.1532-5415.2010.02833.x CrossRefPubMedGoogle Scholar
  11. 11.
    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/s10911-012-9266-0 CrossRefPubMedGoogle Scholar
  12. 12.
    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):3560–3564CrossRefPubMedGoogle Scholar
  13. 13.
    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/labinvest.2012.65 CrossRefPubMedGoogle Scholar
  14. 14.
    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):1878–1886PubMedGoogle Scholar
  15. 15.
    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):40–48PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    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/j.jprot.2010.02.019 CrossRefPubMedGoogle Scholar
  17. 17.
    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):1664–1674CrossRefPubMedGoogle Scholar
  18. 18.
    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):2731–2735PubMedGoogle Scholar
  19. 19.
    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):7045–7051CrossRefPubMedGoogle Scholar
  20. 20.
    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):1–10CrossRefPubMedGoogle Scholar
  21. 21.
    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: 10.1158/1535-7163.MCT-09-0960 PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    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):671–680PubMedGoogle Scholar
  23. 23.
    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/blood-2005-04-1422 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    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/pnas.091062498 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    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/nprot.2008.211 CrossRefGoogle Scholar
  26. 26.
    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/nar/gkn923 PubMedCentralCrossRefGoogle Scholar
  27. 27.
    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):1502–1512CrossRefPubMedGoogle Scholar
  28. 28.
    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/s10637-008-9137-0 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    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: 10.1159/000118626 CrossRefPubMedGoogle Scholar
  30. 30.
    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/co.19.879 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    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/cbt.10.6.12611 CrossRefPubMedGoogle Scholar
  32. 32.
    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):4331–4338CrossRefPubMedGoogle Scholar
  33. 33.
    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/cbr.2011.1103 CrossRefPubMedGoogle Scholar
  34. 34.
    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/s00280-011-1563-6 CrossRefPubMedGoogle Scholar
  35. 35.
    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):281–288CrossRefPubMedGoogle Scholar
  36. 36.
    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/sj.bjc.6604100 PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    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):623–628PubMedGoogle Scholar
  38. 38.
    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/gutjnl-2011-301585 PubMedCentralPubMedGoogle Scholar
  39. 39.
    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):1596–1603PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    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: 10.1158/1078-0432.CCR-11-0078 PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    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):904–916CrossRefPubMedGoogle Scholar
  42. 42.
    Tam L, McGlynn LM, Traynor P, Mukherjee R, Bartlett JM, Edwards J (2007) Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer 97(3):378–383. doi: 10.1038/sj.bjc.6603871 PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Chang YM, Kung HJ, Evans CP (2007) Nonreceptor tyrosine kinases in prostate cancer. Neoplasia 9(2):90–100PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    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/gcc.20948 CrossRefPubMedGoogle Scholar
  45. 45.
    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: 10.1158/1078-0432.CCR-09-2261 PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    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/iub.472 CrossRefPubMedGoogle Scholar
  47. 47.
    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):12917–12922PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    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/j.canlet.2012.11.055 PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Chabner BA, Roberts TG Jr (2005) Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 5(1):65–72. doi: 10.1038/nrc1529 CrossRefPubMedGoogle Scholar
  50. 50.
    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/sj.bjc.6604510 PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Bock C, Lengauer T (2012) Managing drug resistance in cancer: lessons from HIV therapy. Nat Rev Cancer 12(7):494–501. doi: 10.1038/nrc3297 CrossRefPubMedGoogle Scholar
  52. 52.
    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):407–420PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    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/j.ccr.2009.01.021 PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    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):220–231PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    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: 10.1158/1535-7163.MCT-11-0058 CrossRefPubMedGoogle Scholar
  56. 56.
    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: 10.1158/1535-7163.MCT-10-0249 CrossRefPubMedGoogle Scholar
  57. 57.
    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–R24PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    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):5365–5373CrossRefPubMedGoogle Scholar
  59. 59.
    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/jama.2011.51 CrossRefPubMedGoogle Scholar
  60. 60.
    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: 10.1158/1078-0432.CCR-09-0095 PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    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/pgm.2013.01.2628 CrossRefPubMedGoogle Scholar
  62. 62.
    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):1–9PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Annabelle Chow
    • 1
  • Amy Wong
    • 1
  • Giulio Francia
    • 2
  • Shan Man
    • 1
  • Robert S. Kerbel
    • 1
  • Urban Emmenegger
    • 1
    • 3
    • 4
    Email author
  1. 1.Biological Sciences Platform, Sunnybrook Research Institute, Sunnybrook Health Sciences CentreUniversity of TorontoTorontoCanada
  2. 2.Biological SciencesUniversity of Texas El PasoEl PasoUSA
  3. 3.Division of Medical Oncology, Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences CentreUniversity of TorontoTorontoCanada
  4. 4.Sunnybrook Health Sciences Centre T2-054TorontoCanada

Personalised recommendations