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From Molecular to Modular Tumor Therapy pp 243–262Cite as

The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment

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Part of the book series: The Tumor Microenvironment ((TTME,volume 3))

Abstract

The cyclic administration of conventional (i.e., maximum ­tolerated dose [MTD]) chemotherapy targets primarily the tumor cell population. In contrast, chemotherapeutics used at lower doses but on a more frequent basis, and without treatment-free breaks, preferentially affect the tumor vasculature. This so-called low-dose metronomic (LDM) form of chemotherapy administration can be considered as a complementary and/or alternative form of antiangiogenic therapy to the use of targeted antiangiogenic agents such as antibodies or small molecule drugs that interfere with vascular endothelial growth factor (VEGF) pathways. However, it becomes increasingly clear that LDM chemotherapy affects also aspects of the tumor microenvironment other than angiogenesis such as immune responses. Herein, we summarize the complex effects of LDM chemotherapy on the tumor microenvironment, with special emphasis on angiogenesis. We also compare the effects of LDM versus MTD chemotherapy. Finally, we outline how pharmacogenetic characteristics of the tumor host and microenvironment may be exploited in the future to predict response to LDM therapy.

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References

  1. Allegrini G, Falcone A, Fioravanti A, Barletta MT, Orlandi P, Loupakis F, Cerri E, Masi G, Di Paolo A, Kerbel RS, Danesi R, Del Tacca M, Bocci G (2008) A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br J Cancer 98: 1312–1319

    Article  PubMed  CAS  Google Scholar 

  2. Banissi C, Ghiringhelli F, Chen L, Carpentier AF (2009) Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58: 1627–1634

    Article  PubMed  CAS  Google Scholar 

  3. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8: 592–603

    Article  PubMed  CAS  Google Scholar 

  4. Bertolini F, Mancuso P, Shaked Y, Kerbel RS (2007) Molecular and cellular biomarkers for angiogenesis in clinical oncology. Drug Discov Today 12: 806–812

    Article  PubMed  CAS  Google Scholar 

  5. Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63: 4342–4346

    PubMed  CAS  Google Scholar 

  6. Bertolini F, Shaked Y, Mancuso P, Kerbel RS (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6: 835–845

    Article  PubMed  CAS  Google Scholar 

  7. Blansfield JA, Caragacianu D, Alexander HR, 3rd, Tangrea MA, Morita SY, Lorang D, Schafer P, Muller G, Stirling D, Royal RE, Libutti SK (2008) Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clin Cancer Res 14: 270–280

    Article  PubMed  CAS  Google Scholar 

  8. Bocci G, Falcone A, Fioravanti A, Orlandi P, Di Paolo A, Fanelli G, Viacava P, Naccarato AG, Kerbel RS, Danesi R, Del Tacca M, Allegrini G (2008) Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer 98: 1619–1629

    Article  PubMed  CAS  Google Scholar 

  9. 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 USA 100: 12917–12922

    Article  PubMed  CAS  Google Scholar 

  10. Bocci G, Nicolaou KC, Kerbel RS (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62: 6938–6943

    PubMed  CAS  Google Scholar 

  11. Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M (2005) Cyclophosphamide-methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 16: 1243–1252

    Article  PubMed  CAS  Google Scholar 

  12. Bornstein P (1995) Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol 130: 503–506

    Article  PubMed  CAS  Google Scholar 

  13. 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: 3623–3628

    Article  PubMed  CAS  Google Scholar 

  14. Briasoulis E, Pappas P, Puozzo C, Tolis C, Fountzilas G, Dafni U, Marselos M, Pavlidis N (2009) Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 15: 6454–6461

    Article  PubMed  CAS  Google Scholar 

  15. 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: 1878–1886

    PubMed  CAS  Google Scholar 

  16. Buckstein R, Kerbel RS, Shaked Y, Nayar R, Foden C, Turner R, Lee CR, Taylor D, Zhang L, Man S, Baruchel S, Stempak D, Bertolini F, Crump M (2006) High-Dose celecoxib and metronomic “low-dose” cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin’s lymphoma. Clin Cancer Res 12: 5190–5198

    Article  PubMed  CAS  Google Scholar 

  17. Chen HX, Cleck JN (2009) Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6: 465–477

    Article  PubMed  CAS  Google Scholar 

  18. Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nole F, Viale G, Goldhirsch A (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17: 232–238

    Article  PubMed  CAS  Google Scholar 

  19. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de BF, Viale G, Goldhirsch A (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13: 73–80

    Article  PubMed  CAS  Google Scholar 

  20. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30: 1073–1081

    Article  PubMed  CAS  Google Scholar 

  21. Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K (2006) The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol 58: 354–360

    Article  PubMed  CAS  Google Scholar 

  22. Dedes KJ, Matter-Walstra K, Schwenkglenks M, Pestalozzi BC, Fink D, Brauchli P, Szucs TD (2009) Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation. Eur J Cancer 45: 1397–1406

    Article  PubMed  CAS  Google Scholar 

  23. Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26: 4899–4905

    Article  PubMed  CAS  Google Scholar 

  24. Doggrell SA (2009) Clinical efficacy and safety of zoledronic acid in prostate and breast cancer. Expert Rev Anticancer Ther 9: 1211–1218

    Article  PubMed  CAS  Google Scholar 

  25. Doloff JC, Waxman DJ (2009) Metronomic cyclophosphamide induces macrophage recruitment in regressing human and rat gliosarcoma xenografts. Proceedings of the AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics: 108

    Google Scholar 

  26. Drake CG (2009) Immunotherapy for prostate cancer: walk, don’t run. J Clin Oncol 27: 4035–4037

    Article  PubMed  CAS  Google Scholar 

  27. 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: 904–916

    Article  PubMed  Google Scholar 

  28. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8: 579–591

    Article  PubMed  CAS  Google Scholar 

  29. Emadi A, Jones RJ, Brodsky RA (2009) Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6: 638–647

    Article  PubMed  CAS  Google Scholar 

  30. Emmenegger U, Kerbel RS (2007) Five years of clinical experience with metronomic chemotherapy: achievements and perspectives. Onkologie 30: 606–608

    Article  PubMed  Google Scholar 

  31. Emmenegger U, Man S, Shaked Y, Francia G, Wong JW, Hicklin DJ, Kerbel RS (2004) 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. Cancer Res 64: 3994–4000

    Article  PubMed  CAS  Google Scholar 

  32. 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: 1664–1674

    Article  PubMed  CAS  Google Scholar 

  33. Emmenegger U, Shaked Y, Man S, Bocci G, Spasojevic I, Francia G, Kouri A, Coke R, Cruz-Munoz W, Ludeman SM, Colvin OM, Kerbel RS (2007) Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol Cancer Ther 6: 2280–2289

    Article  PubMed  CAS  Google Scholar 

  34. Falanga A (2005) Mechanisms of thrombosis in cancer. Thromb Res 115(Suppl 1): 21–24

    PubMed  Google Scholar 

  35. Fioravanti A, Canu B, Ali G, Orlandi P, Allegrini G, Di Desidero T, Emmenegger U, Fontanini G, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer. Eur J Pharmacol 619: 8–14

    Article  PubMed  CAS  Google Scholar 

  36. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186

    Article  PubMed  CAS  Google Scholar 

  37. Folkman J (2003) Angiogenesis and apoptosis. Semin Cancer Biol 13: 159–167

    Article  PubMed  CAS  Google Scholar 

  38. Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, Bursi S, Allegrini G, Fontana E, Di Marsico R, Antonuzzo A, D’Arcangelo M, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15: 4954–4962

    Article  PubMed  CAS  Google Scholar 

  39. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, Groshen S, Swenson S, Markland F, Gandara D, Scudder S, Morgan R, Chen H, Lenz HJ, Oza AM (2008) Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26: 76–82

    Article  PubMed  CAS  Google Scholar 

  40. Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69: 4894–4903

    Article  PubMed  CAS  Google Scholar 

  41. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34: 336–344

    Article  PubMed  CAS  Google Scholar 

  42. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B (2007) Metronomic cyclophosphamide regimen selectively depletes CD4(+)CD25 (+) regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56: 641–648

    Article  PubMed  CAS  Google Scholar 

  43. Gille J, Spieth K, Kaufmann R (2005) Metronomic low-dose chemotherapy as antiangiogenic therapeutic strategy for cancer. J Dtsch Dermatol Ges 3: 26–32

    Article  PubMed  Google Scholar 

  44. Grimbert P, Bouguermouh S, Baba N, Nakajima T, Allakhverdi Z, Braun D, Saito H, Rubio M, Delespesse G, Sarfati M (2006) Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation. J Immunol 177: 3534–3541

    PubMed  CAS  Google Scholar 

  45. Grothey A, Galanis E (2009) Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 6: 507–518

    Article  PubMed  CAS  Google Scholar 

  46. Gupta K, Gupta P, Wild R, Ramakrishnan S, Hebbel RP (1999) Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis. Angiogenesis 3: 147–158

    Article  PubMed  CAS  Google Scholar 

  47. Haddad TC, Greeno EW (2006) Chemotherapy-induced thrombosis. Thromb Res 118: 555–568

    Article  PubMed  CAS  Google Scholar 

  48. Hahnfeldt P, Folkman J, Hlatky L (2003) Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 220: 545–554

    Article  PubMed  Google Scholar 

  49. Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, Sudhakar A, Kalluri R (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64: 1570–1574

    Article  PubMed  CAS  Google Scholar 

  50. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70

    Article  PubMed  CAS  Google Scholar 

  51. Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V (2003) Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 63: 8408–8413

    PubMed  CAS  Google Scholar 

  52. Hopkins AL, Mason JS, Overington JP (2006) Can we rationally design promiscuous drugs? Curr Opin Struct Biol 16: 127–136

    Article  PubMed  CAS  Google Scholar 

  53. Ivy SP, Wick JY, Kaufman BM (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6: 569–579

    Article  PubMed  CAS  Google Scholar 

  54. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6: 327–338

    Article  PubMed  CAS  Google Scholar 

  55. Johnson JA, Cavallari LH (2005) Cardiovascular pharmacogenomics. Exp Physiol 90: 283–289

    Article  PubMed  CAS  Google Scholar 

  56. Jubb AM, Oates AJ, Holden S, Koeppen H (2006) Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 6: 626–635

    Article  PubMed  CAS  Google Scholar 

  57. 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: 281–288

    Article  PubMed  CAS  Google Scholar 

  58. 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: 1713–1721

    Article  PubMed  CAS  Google Scholar 

  59. Kerbel RS (1991) Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13: 31–36

    Article  PubMed  CAS  Google Scholar 

  60. Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312: 1171–1175

    Article  PubMed  CAS  Google Scholar 

  61. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358: 2039–2049

    Article  PubMed  CAS  Google Scholar 

  62. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4: 423–436

    Article  PubMed  CAS  Google Scholar 

  63. Kieran MW (2004) Anti-angiogenic chemotherapy in central nervous system tumors. Cancer Treat Res 117: 337–349

    Article  PubMed  CAS  Google Scholar 

  64. 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: R15–24

    Article  PubMed  CAS  Google Scholar 

  65. Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13: 472–482

    Article  PubMed  CAS  Google Scholar 

  66. Kuenen BC, Rosen L, Smit EF, Parson MR, Levi M, Ruijter R, Huisman H, Kedde MA, Noordhuis P, van der Vijgh WJ, Peters GJ, Cropp GF, Scigalla P, Hoekman K, Pinedo HM, Giaccone G (2002) Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20: 1657–1667

    Article  PubMed  CAS  Google Scholar 

  67. Lake RA, Robinson BW (2005) Immunotherapy and chemotherapy – a practical partnership. Nat Rev Cancer 5: 397–405

    Article  PubMed  CAS  Google Scholar 

  68. Lam T, Hetherington JW, Greenman J, Maraveyas A (2006) From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials. Anticancer Drugs 17: 113–121

    Article  PubMed  CAS  Google Scholar 

  69. Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA 106: 2353–2358

    Article  PubMed  Google Scholar 

  70. Lev DC, Ruiz M, Mills L, McGary EC, Price JE, Bar-Eli M (2003) Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther 2: 753–763

    PubMed  CAS  Google Scholar 

  71. Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, Pandha H (2007) Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol 177: 2136–2140; discussion 2140

    Article  PubMed  CAS  Google Scholar 

  72. Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136: 823–837

    Article  PubMed  CAS  Google Scholar 

  73. Ma J, Waxman DJ (2007) Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment. Mol Cancer Ther 6: 2879–2890

    Article  PubMed  CAS  Google Scholar 

  74. Ma J, Waxman DJ (2008) Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther 7: 79–89

    Article  PubMed  CAS  Google Scholar 

  75. 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: 5365–5373

    Article  PubMed  CAS  Google Scholar 

  76. Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G, Agliano A, Goldhirsch A, Shaked Y, Kerbel RS, Bertolini F (2006) Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108: 452–459

    Article  PubMed  CAS  Google Scholar 

  77. Mantovani A (2009) Cancer: inflaming metastasis. Nature 457: 36–37

    Article  PubMed  CAS  Google Scholar 

  78. Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70: 325–330

    Article  PubMed  CAS  Google Scholar 

  79. Miller KD, Sweeney CJ, Sledge GW, Jr. (2001) Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19: 1195–1206

    PubMed  CAS  Google Scholar 

  80. Mills PJ, Parker B, Jones V, Adler KA, Perez CJ, Johnson S, Cohen-Zion M, Marler M, Sadler GR, Dimsdale JE, Ancoli-Israel S (2004) The effects of standard anthracycline-based chemotherapy on soluble ICAM-1 and vascular endothelial growth factor levels in breast cancer. Clin Cancer Res 10: 4998–5003

    Article  PubMed  CAS  Google Scholar 

  81. Miyahara Y, Yoshida S, Motoyama S, Tateiwa Y, Hamana S, Maruo T (2004) Effect of cis-diammine dichloroplatinum on vascular endothelial growth factor expression in uterine cervical carcinoma. Eur J Gynaecol Oncol 25: 33–39

    PubMed  CAS  Google Scholar 

  82. Moodley Y, Rigby P, Bundell C, Bunt S, Hayashi H, Misso N, McAnulty R, Laurent G, Scaffidi A, Thompson P, Knight D (2003) Macrophage recognition and phagocytosis of apoptotic fibroblasts is critically dependent on fibroblast-derived thrombospondin 1 and CD36. Am J Pathol 162: 771–779

    Article  PubMed  CAS  Google Scholar 

  83. Munoz R, Shaked Y, Bertolini F, Emmenegger U, Man S, Kerbel RS (2005) Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. Breast 14: 466–479

    Google Scholar 

  84. Ooyama A, Oka T, Zhao HY, Yamamoto M, Akiyama S, Fukushima M (2008) Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts. Cancer Lett 267: 26–36

    Article  PubMed  CAS  Google Scholar 

  85. Partridge AH, Avorn J, Wang PS, Winer EP (2002) Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 94: 652–661

    Article  PubMed  Google Scholar 

  86. Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23: 939–952

    Article  PubMed  CAS  Google Scholar 

  87. Price KN, Goldhirsch A (2005) Clinical trial update: international breast cancer study group. Breast Cancer Res 7: 252–254

    Article  PubMed  Google Scholar 

  88. Quesada AJ, Nelius T, Yap R, Zaichuk TA, Alfranca A, Filleur S, Volpert OV, Redondo JM (2005) In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment. Cell Death Differ 12: 649–658

    Article  PubMed  CAS  Google Scholar 

  89. Rabascio C, Muratori E, Mancuso P, Calleri A, Raia V, Foutz T, Cinieri S, Veronesi G, Pruneri G, Lampertico P, Iavarone M, Martinelli G, Goldhirsch A, Bertolini F (2004) Assessing tumor angiogenesis: increased circulating VE-cadherin RNA in patients with cancer indicates viability of circulating endothelial cells. Cancer Res 64: 4373–4377

    Article  PubMed  CAS  Google Scholar 

  90. Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12: 74–80

    Article  PubMed  CAS  Google Scholar 

  91. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64: 6845–6848

    Article  PubMed  CAS  Google Scholar 

  92. Reichle A, Bross K, Vogt T, Bataille F, Wild P, Berand A, Krause SW, Andreesen R (2004) Pioglitazone and rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma. Cancer 101: 2247–2256

    Article  PubMed  CAS  Google Scholar 

  93. Reichle A, Vogt T (2008) Systems biology: a therapeutic target for tumor therapy. Cancer Microenviron 1: 159–170

    Article  PubMed  CAS  Google Scholar 

  94. Reichle A, Vogt T, Coras B, Terheyden P, Neuber K, Trefzer U, Schultz E, Berand A, Brocker EB, Landthaler M, Andreesen R (2007) Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial. Melanoma Res 17: 360–364

    Article  PubMed  CAS  Google Scholar 

  95. Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E (2000) A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res 37: 443–448

    Article  PubMed  CAS  Google Scholar 

  96. Riedel F, Gotte K, Goessler U, Sadick H, Hormann K (2004) Targeting chemotherapy-induced VEGF up-regulation by VEGF antisense oligonucleotides in HNSCC cell lines. Anticancer Res 24: 2179–2183

    PubMed  CAS  Google Scholar 

  97. Rozkova D, Tiserova H, Fucikova J, Last’ovicka J, Podrazil M, Ulcova H, Budinsky V, Prausova J, Linke Z, Minarik I, Sediva A, Spisek R, Bartunkova J (2009) FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clin Immunol 131: 1–10

    Article  PubMed  CAS  Google Scholar 

  98. Schultheis AM, Lurje G, Rhodes KE, Zhang W, Yang D, Garcia AA, Morgan R, Gandara D, Scudder S, Oza A, Hirte H, Fleming G, Roman L, Lenz HJ (2008) Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin Cancer Res 14: 7554–7563

    Article  PubMed  CAS  Google Scholar 

  99. Sessa C, Guibal A, Del Conte G, Ruegg C (2008) Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat Clin Pract Oncol 5: 378–391

    Article  PubMed  CAS  Google Scholar 

  100. Shahab N, Haider S, Doll DC (2006) Vascular toxicity of antineoplastic agents. Semin Oncol 33: 121–138

    Article  PubMed  CAS  Google Scholar 

  101. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313: 1785–1787

    Article  PubMed  CAS  Google Scholar 

  102. Shaked Y, Emmenegger U, Francia G, Chen L, Lee CR, Man S, Paraghamian A, Ben-David Y, Kerbel RS (2005a) Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res 65: 7045–7051

    Article  PubMed  CAS  Google Scholar 

  103. Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y, Kerbel RS (2005b) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106: 3058–3061

    Article  PubMed  CAS  Google Scholar 

  104. Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Strieter RM, Bertolini F, Voest EE, Benezra R, Kerbel RS (2008) Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14: 263–273

    Article  PubMed  CAS  Google Scholar 

  105. Shaked Y, Tang T, Woloszynek J, Daenen LG, Man S, Xu P, Cai SR, Arbeit JM, Voest EE, Chaplin DJ, Smythe J, Harris A, Nathan P, Judson I, Rustin G, Bertolini F, Link DC, Kerbel RS (2009) Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents. Cancer Res 69: 7524–7528

    Article  PubMed  CAS  Google Scholar 

  106. Sobrero A, Bruzzi P (2009) Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval. J Clin Oncol 27: 5868–5873

    Article  PubMed  Google Scholar 

  107. Sobrero AF, Aschele C, Bertino JR (1997) Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. J Clin Oncol 15: 368–381

    PubMed  CAS  Google Scholar 

  108. Steinbild S, Arends J, Medinger M, Haring B, Frost A, Drevs J, Unger C, Strecker R, Hennig J, Mross K (2007) Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients – results of a phase II study. Onkologie 30: 629–635

    Article  PubMed  CAS  Google Scholar 

  109. Takahashi Y, Mai M, Sawabu N, Nishioka K (2005) A pilot study of individualized maximum repeatable dose (iMRD), a new dose finding system, of weekly gemcitabine for patients with metastatic pancreas cancer. Pancreas 30: 206–210

    Article  PubMed  CAS  Google Scholar 

  110. Tan K, Lawler J (2009) The interaction of Thrombospondins with extracellular matrix proteins. J Cell Commun Signal 3(3/4): 177–187

    Google Scholar 

  111. Tanaka H, Matsushima H, Mizumoto N, Takashima A (2009a) Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res 69: 6978–6986

    Article  PubMed  CAS  Google Scholar 

  112. Tanaka H, Matsushima H, Nishibu A, Clausen BE, Takashima A (2009b) Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res 69: 6987–6994

    Article  PubMed  CAS  Google Scholar 

  113. Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS (2002) A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA 99: 4349–4354

    Article  PubMed  CAS  Google Scholar 

  114. Ueno A, Miwa Y, Miyoshi K, Horiguchi T, Inoue H, Ruspita I, Abe K, Yamashita K, Hayashi E, Noma T (2006) Constitutive expression of thrombospondin 1 in MC3T3-E1 osteoblastic cells inhibits mineralization. J Cell Physiol 209: 322–332

    Article  PubMed  CAS  Google Scholar 

  115. Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, Amin M, Bouck NP (2002) Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 8: 349–357

    Article  PubMed  CAS  Google Scholar 

  116. 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: 1368–1374

    Article  PubMed  CAS  Google Scholar 

  117. Wong NS, Buckman RA, Clemons M, Verma S, Dent S, Trudeau ME, Roche K, Ebos J, Kerbel R, Deboer GE, Sutherland DJ, Emmenegger U, Slingerland J, Gardner S, Pritchard KI (2010) Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. J Clin Oncol 28:723–730

    Google Scholar 

  118. Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV (2005) Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 11: 6678–6685

    Article  PubMed  CAS  Google Scholar 

  119. Yesner LM, Huh HY, Pearce SF, Silverstein RL (1996) Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler Thromb Vasc Biol 16: 1019–1025

    Article  PubMed  CAS  Google Scholar 

  120. Young SD, Whissell M, Noble JC, Cano PO, Lopez PG, Germond CJ (2006) Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res 12: 3092–3098

    Article  PubMed  CAS  Google Scholar 

  121. Zhao D, Jiang L, Hahn EW, Mason RP (2005) Continuous low-dose (metronomic) chemotherapy on rat prostate tumors evaluated using MRI in vivo and comparison with histology. Neoplasia 7: 678–687

    Article  PubMed  Google Scholar 

  122. Zhao HY, Ooyama A, Yamamoto M, Ikeda R, Haraguchi M, Tabata S, Furukawa T, Che XF, Zhang S, Oka T, Fukushima M, Nakagawa M, Ono M, Kuwano M, Akiyama S (2008) Molecular basis for the induction of an angiogenesis inhibitor, thrombospondin-1, by 5-fluorouracil. Cancer Res 68: 7035–7041

    Article  PubMed  CAS  Google Scholar 

  123. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8: 59–73

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to C. Norman for his excellent secretarial and editorial assistance. Urban Emmenegger is supported by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Guido Bocci is supported by a grant from the Italian Association for Cancer Research (AIRC).

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Authors and Affiliations

  1. Sunnybrook Odette Cancer Centre, Division of Medical Oncology, Department of Medicine & Sunnybrook Research Institute, Division of Molecular and Cellular Biology Research, Sunnybrook Health Science Centre, University of Toronto, 2075 Bayview Avenue, M4N3M5, Toronto, ON, Canada

    Urban Emmenegger

  2. Division of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, M4N3M5, Toronto, ON, Canada

    Annabelle Chow

  3. Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa & Istituto Toscano Tumori (ITT), Via Roma, 55, I-56126, Pisa, Italy

    Guido Bocci

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  1. Urban Emmenegger
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Correspondence to Urban Emmenegger .

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  1. , Department of Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, 93042, Germany

    Albrecht Reichle

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Emmenegger, U., Chow, A., Bocci, G. (2010). The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment. In: Reichle, A. (eds) From Molecular to Modular Tumor Therapy. The Tumor Microenvironment, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9531-2_11

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