Skip to main content
SpringerLink
Log in

Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments

  • Chapter
  • First Online:
Metronomic Chemotherapy

Abstract

Microtubule-targeting agents (MTAs) are amongst the most successful chemotherapeutic drugs commonly used in the clinic for the treatment of human cancers. Although originally administered at or close to the maximum tolerated dose once every 3 weeks, the discovery of their potent antiangiogenic properties at the end of the 1990s has led to the re-evaluation of treatment protocols. Nowadays, MTAs are often administered at lower doses either weekly or even more frequently following a metronomic schedule, thus leading to increased efficacy and decreased toxicity. In this chapter, we present an overview of the in vitro and in vivo studies that have contributed to the development of MTA-based metronomic chemotherapy protocols and increased our understanding of their mechanisms of action. First, we discuss the complex cellular and molecular mechanisms involved in the antiangiogenic activity of MTAs. We also present their effects on the immune system, which may contribute to the antitumour efficacy of MTA-based metronomic chemotherapy. Then, we review the results obtained with this type of therapeutic approach in preclinical models of human cancer, focusing on the most promising combination treatments. Finally, we oversee the future developments in this field in terms of new MTAs and novel formulations currently in development with the aims to improve efficacy and bioavailability while increasing tumour targeting and specificity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265

    CAS  PubMed  Google Scholar 

  2. Jordan MA, Kamath K (2007) How do microtubule-targeted drugs work? An overview. Curr Cancer Drug Targets 7:730–742

    CAS  PubMed  Google Scholar 

  3. Pasquier E, Kavallaris M (2008) Microtubules: a dynamic target in cancer therapy. IUBMB Life 60:165–170

    CAS  PubMed  Google Scholar 

  4. Dumontet C, Jordan MA (2010) Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 9:790–803

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Pasquier E, Honore S, Braguer D (2006) Microtubule-targeting agents in angiogenesis: where do we stand? Drug Resist Updat 9:74–86

    CAS  PubMed  Google Scholar 

  6. Pasquier E, Andre N, Braguer D (2007) Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment. Curr Cancer Drug Targets 7:566–581

    CAS  PubMed  Google Scholar 

  7. Schwartz EL (2009) Antivascular actions of microtubule-binding drugs. Clin Cancer Res 15:2594–2601

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Bocci G, Di Paolo A, Danesi R (2013) The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis 16:481–492

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Pasquier E, Sinnappan S, Munoz MA, Kavallaris M (2010) ENMD-1198, a new analogue of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties. Mol Cancer Ther 9:1408–1418

    CAS  PubMed  Google Scholar 

  10. Honore S, Pasquier E, Braguer D (2005) Understanding microtubule dynamics for improved cancer therapy. Cell Mol Life Sci 62:3039–3056

    CAS  PubMed  Google Scholar 

  11. Bayless KJ, Johnson GA (2011) Role of the cytoskeleton in formation and maintenance of angiogenic sprouts. J Vasc Res 48:369–385

    PubMed Central  PubMed  Google Scholar 

  12. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, Giavazzi R, Taraboletti G (1996) The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2:1843–1849

    CAS  PubMed  Google Scholar 

  13. Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Ria R, Pellegrino A, Dammacco F (1999) Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 94:4143–4155

    CAS  PubMed  Google Scholar 

  14. Hayot C, Farinelle S, De Decker R, Decaestecker C, Darro F, Kiss R, Van Damme M (2002) In vitro pharmacological characterizations of the anti-angiogenic and anti-tumor cell migration properties mediated by microtubule-affecting drugs, with special emphasis on the organization of the actin cytoskeleton. Int J Oncol 21:417–425

    CAS  PubMed  Google Scholar 

  15. 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

    CAS  PubMed  Google Scholar 

  16. Hotchkiss KA, Ashton AW, Mahmood R, Russell RG, Sparano JA, Schwartz EL (2002) Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther 1:1191–1200

    CAS  PubMed  Google Scholar 

  17. Wang J, Lou P, Lesniewski R, Henkin J (2003) Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs 14:13–19

    PubMed  Google Scholar 

  18. Pasquier E, Carre M, Pourroy B, Camoin L, Rebai O, Briand C, Braguer D (2004) Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. Mol Cancer Ther 3:1301–1310

    CAS  PubMed  Google Scholar 

  19. Pourroy B, Honore S, Pasquier E, Bourgarel-Rey V, Kruczynski A, Briand C, Braguer D (2006) Antiangiogenic concentrations of vinflunine increase the interphase microtubule dynamics and decrease the motility of endothelial cells. Cancer Res 66:3256–3263

    CAS  PubMed  Google Scholar 

  20. Tozer GM, Kanthou C, Baguley BC (2005) Disrupting tumour blood vessels. Nat Rev Cancer 5:423–435

    CAS  PubMed  Google Scholar 

  21. Gotlieb AI, May LM, Subrahmanyan L, Kalnins VI (1981) Distribution of microtubule organizing centers in migrating sheets of endothelial cells. J Cell Biol 91:589–594

    CAS  PubMed  Google Scholar 

  22. Ueda M, Graf R, MacWilliams HK, Schliwa M, Euteneuer U (1997) Centrosome positioning and directionality of cell movements. Proc Natl Acad Sci U S A 94:9674–9678

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Kamath K, Smiyun G, Wilson L, Jordan MA (2013) Mechanisms of inhibition of endothelial cell migration by taxanes. Cytoskeleton (Hoboken) 71(1):46–60

    Google Scholar 

  24. Pasquier E, Honore S, Pourroy B, Jordan MA, Lehmann M, Briand C, Braguer D (2005) Antiangiogenic concentrations of paclitaxel induce an increase in microtubule dynamics in endothelial cells but not in cancer cells. Cancer Res 65:2433–2440

    CAS  PubMed  Google Scholar 

  25. Honore S, Pagano A, Gauthier G, Bourgarel-Rey V, Verdier-Pinard P, Civiletti K, Kruczynski A, Braguer D (2008) Antiangiogenic vinflunine affects EB1 localization and microtubule targeting to adhesion sites. Mol Cancer Ther 7:2080–2089

    CAS  PubMed  Google Scholar 

  26. Rovini A, Gauthier G, Berges R, Kruczynski A, Braguer D, Honore S (2013) Anti-migratory effect of vinflunine in endothelial and glioblastoma cells is associated with changes in EB1 C-terminal detyrosinated/tyrosinated status. PLoS One 8:e65694

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Ganguly A, Yang H, Zhang H, Cabral F, Patel KD (2013) Microtubule dynamics control tail retraction in migrating vascular endothelial cells. Mol Cancer Ther 12:2837–2846

    CAS  PubMed  Google Scholar 

  28. Bijman MN, van Nieuw Amerongen GP, Laurens N, van Hinsbergh VW, Boven E (2006) Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton. Mol Cancer Ther 5:2348–2357

    CAS  PubMed  Google Scholar 

  29. Lopez de Heredia M, Jansen RP (2004) mRNA localization and the cytoskeleton. Curr Opin Cell Biol 16:80–85

    PubMed  Google Scholar 

  30. Bonezzi K, Belotti D, North BJ, Ghilardi C, Borsotti P, Resovi A, Ubezio P, Riva A, Giavazzi R, Verdin E, Taraboletti G (2012) Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies. Neoplasia 14:846–854

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, Willard MT, Zhong H, Simons JW, Giannakakou P (2003) 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 3:363–375

    CAS  PubMed  Google Scholar 

  32. Escuin D, Kline ER, Giannakakou P (2005) Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1 alpha accumulation and activity by disrupting microtubule function. Cancer Res 65:9021–9028

    CAS  PubMed  Google Scholar 

  33. Moser C, Lang SA, Mori A, Hellerbrand C, Schlitt HJ, Geissler EK, Fogler WE, Stoeltzing O (2008) ENMD-1198, a novel tubulin-binding agent reduces HIF-1 alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer 8:206

    PubMed Central  PubMed  Google Scholar 

  34. Hata K, Osaki M, Dhar DK, Nakayama K, Fujiwaki R, Ito H, Nagasue N, Miyazaki K (2004) Evaluation of the antiangiogenic effect of Taxol in a human epithelial ovarian carcinoma cell line. Cancer Chemother Pharmacol 53:68–74

    CAS  PubMed  Google Scholar 

  35. Thijssen VL, Brandwijk RJ, Dings RP, Griffioen AW (2004) Angiogenesis gene expression profiling in xenograft models to study cellular interactions. Exp Cell Res 299:286–293

    CAS  PubMed  Google Scholar 

  36. Loo WT, Fong JH, Cheung MN, Chow LW (2005) The efficacy of Paclitaxel on solid tumour analysed by ATP bioluminescence assay and VEGF expression: a translational research study. Biomed Pharmacother 59(Suppl 2):S337–S339

    CAS  PubMed  Google Scholar 

  37. 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 68:879–887

    CAS  PubMed  Google Scholar 

  38. Aktas SH, Akbulut H, Akgun N, Icli F (2012) Low dose chemotherapeutic drugs without overt cytotoxic effects decrease the secretion of VEGF by cultured human tumor cells: a tentative relationship between drug type and tumor cell type response. Cancer Biomark 12:135–140

    CAS  PubMed  Google Scholar 

  39. Murtagh J, Lu H, Schwartz EL (2006) Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock protein 90 degradation. Cancer Res 66:8192–8199

    CAS  PubMed  Google Scholar 

  40. 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 100:12917–12922

    CAS  PubMed Central  PubMed  Google Scholar 

  41. 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

    CAS  PubMed  Google Scholar 

  42. Zhang M, Tao W, Pan S, Sun X, Jiang H (2009) Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts. Anticancer Drugs 20:355–363

    PubMed  Google Scholar 

  43. Jiang H, Tao W, Zhang M, Pan S, Kanwar JR, Sun X (2010) Low-dose metronomic paclitaxel chemotherapy suppresses breast tumors and metastases in mice. Cancer Invest 28:74–84

    CAS  PubMed  Google Scholar 

  44. Meissner M, Pinter A, Michailidou D, Hrgovic I, Kaprolat N, Stein M, Holtmeier W, Kaufmann R, Gille J (2008) Microtubule-targeted drugs inhibit VEGF receptor-2 expression by both transcriptional and post-transcriptional mechanisms. J Invest Dermatol 128:2084–2091

    CAS  PubMed  Google Scholar 

  45. Andre N, Carre M, Pasquier E (2014) Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol 11:413–431

    CAS  PubMed  Google Scholar 

  46. Park D, Dilda PJ (2010) Mitochondria as targets in angiogenesis inhibition. Mol Aspects Med 31:113–131

    CAS  PubMed  Google Scholar 

  47. Merchan JR, Jayaram DR, Supko JG, He X, Bubley GJ, Sukhatme VP (2005) Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: potentiation by Cox-2 inhibition. Int J Cancer 113:490–498

    CAS  PubMed  Google Scholar 

  48. Pasquier E, Tuset MP, Street J, Sinnappan S, MacKenzie KL, Braguer D, Andre N, Kavallaris M (2013) Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells. Angiogenesis 16:373–386

    CAS  PubMed Central  PubMed  Google Scholar 

  49. 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 106:3058–3061

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Muta M, Yanagawa T, Sai Y, Saji S, Suzuki E, Aruga T, Kuroi K, Matsumoto G, Toi M, Nakashima E (2009) Effect of low-dose Paclitaxel and docetaxel on endothelial progenitor cells. Oncology 77:182–191

    CAS  PubMed  Google Scholar 

  52. Kavallaris M (2010) Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 10:194–204

    CAS  PubMed  Google Scholar 

  53. Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465

    PubMed  Google Scholar 

  54. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689–3697

    CAS  PubMed  Google Scholar 

  55. Vicari AP, Luu R, Zhang N, Patel S, Makinen SR, Hanson DC, Weeratna RD, Krieg AM (2009) Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 58:615–628

    CAS  PubMed  Google Scholar 

  56. Zhu Y, Liu N, Xiong SD, Zheng YJ, Chu YW (2011) CD4 + Foxp3+ regulatory T-cell impairment by paclitaxel is independent of toll-like receptor 4. Scand J Immunol 73:301–308

    CAS  PubMed  Google Scholar 

  57. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY (2010) A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16:4583–4594

    CAS  PubMed  Google Scholar 

  58. Geller MA, Bui-Nguyen TM, Rogers LM, Ramakrishnan S (2010) Chemotherapy induces macrophage chemoattractant protein-1 production in ovarian cancer. Int J Gynecol Cancer 20:918–925

    PubMed  Google Scholar 

  59. Qian DZ, Rademacher BL, Pittsenbarger J, Huang CY, Myrthue A, Higano CS, Garzotto M, Nelson PS, Beer TM (2010) CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel-induced cytotoxicity. Prostate 70:433–442

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, Ochiai A (2009) Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer 125:1276–1284

    CAS  PubMed  Google Scholar 

  61. Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI (2010) Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 120:1111–1124

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Kovarova L, Buchler T, Pour L, Zahradova L, Ocadlikova D, Svobodnik A, Penka M, Vorlicek J, Hajek R (2007) Dendritic cell counts and their subsets during treatment of multiple myeloma. Neoplasma 54:297–303

    CAS  PubMed  Google Scholar 

  63. Shurin GV, Tourkova IL, Kaneno R, Shurin MR (2009) Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol 183:137–144

    CAS  PubMed Central  PubMed  Google Scholar 

  64. John J, Ismail M, Riley C, Askham J, Morgan R, Melcher A, Pandha H (2010) Differential effects of Paclitaxel on dendritic cell function. BMC Immunol 11:14

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Kaneno R, Shurin GV, Tourkova IL, Shurin MR (2009) Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations. J Transl Med 7:58

    PubMed Central  PubMed  Google Scholar 

  68. Wan S, Pestka S, Jubin RG, Lyu YL, Tsai YC, Liu LF (2012) Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One 7:e32542

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Thomas-Schoemann A, Lemare F, Mongaret C, Bermudez E, Chereau C, Nicco C, Dauphin A, Weill B, Goldwasser F, Batteux F, Alexandre J (2011) Bystander effect of vinorelbine alters antitumor immune response. Int J Cancer 129:1511–1518

    CAS  PubMed  Google Scholar 

  70. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G (2012) The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 11:215–233

    CAS  PubMed  Google Scholar 

  71. Nars MS, Kaneno R (2013) Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy. Int J Cancer 132:2471–2478

    CAS  PubMed  Google Scholar 

  72. 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–R24

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D, Kerbel RS (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res 8:221–232

    CAS  PubMed  Google Scholar 

  74. Kruczynski A, Poli M, Dossi R, Chazottes E, Berrichon G, Ricome C, Giavazzi R, Hill BT, Taraboletti G (2006) Anti-angiogenic, vascular-dirsputing and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development. Eur J Cancer 42:2821–2832

    CAS  PubMed  Google Scholar 

  75. Stalder MW, Anthony CT, Woltering EA (2011) Metronomic dosing enhances the anti-angiogenic effect of epothilone B. J Surg Res 169:247–256

    CAS  PubMed Central  PubMed  Google Scholar 

  76. 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

    CAS  PubMed  Google Scholar 

  77. Bradshaw-Pierce EL, Steinhauer CA, Raben D, Gustafson DL (2008) Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma. Mol Cancer Ther 7:3006–3017

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Palmberg E, Johnsen JI, Paulsson J, Gleissman H, Wickstrom M, Edgren M, Ostman A, Kogner P, Lindskog M (2009) Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo. Int J Cancer 124:1227–1234

    CAS  PubMed  Google Scholar 

  79. Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L (2010) Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy. Oncol Rep 24:1049–1058

    CAS  PubMed  Google Scholar 

  80. Berruti A, Sperone P, Ferrero A, Germano A, Ardito A, Priola AM, De Francia S, Volante M, Daffara F, Generali D, Leboulleux S, Perotti P, Baudin E, Papotti M, Terzolo M (2012) Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol 166:451–458

    CAS  PubMed  Google Scholar 

  81. Kerbel RS, Guerin E, Francia G, Xu P, Lee CR, Ebos JM, Man S (2013) Preclinical recapitulation of antiangiogenic drug clinical efficacies using models of early or late stage breast cancer metastatis. Breast 22(Suppl 2):S57–S65

    PubMed  Google Scholar 

  82. Guerin E, Man S, Xu P, Kerbel RS (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73:2743–2748

    CAS  PubMed  Google Scholar 

  83. Andre N, Banavali S, Snihur Y, Pasquier E (2013) Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 14:e239–e248

    PubMed  Google Scholar 

  84. Pasquier E, Ciccolini J, Carre M, Giacometti S, Fanciullino R, Pouchy C, Montero MP, Serdjebi C, Kavallaris M, Andre N (2011) Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2:797–809

    PubMed Central  PubMed  Google Scholar 

  85. Pasquier E, Street J, Pouchy C, Carre M, Gifford AJ, Murray J, Norris MD, Trahair T, Andre N, Kavallaris M (2013) beta-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br J Cancer 108:2485–2494

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Chen CA, Ho CM, Chang MC, Sun WZ, Chen YL, Chiang YC, Syu MH, Hsieh CY, Cheng WF (2010) Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis. Mol Ther 18:1233–1243

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Foy KC, Miller MJ, Moldovan N, Bozanovic T, Carson Iii WE, Kaumaya PT (2012) Immunotherapy with HER-2 and VEGF peptide mimics plus metronomic paclitaxel causes superior antineoplastic effects in transplantable and transgenic mouse models of human breast cancer. Oncoimmunology 1:1004–1016

    PubMed Central  PubMed  Google Scholar 

  88. Hennenfent KL, Govindan R (2006) Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncol 17:735–749

    CAS  PubMed  Google Scholar 

  89. Ng SS, Figg WD, Sparreboom A (2004) Taxane-mediated antiangiogenesis in vitro: influence of formulation vehicles and binding proteins. Cancer Res 64:821–824

    CAS  PubMed  Google Scholar 

  90. 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 12:4331–4338

    CAS  PubMed  Google Scholar 

  91. Cervin C, Tinzl M, Johnsson M, Abrahamsson PA, Tiberg F, Dizeyi N (2010) Properties and effects of a novel liquid crystal nanoparticle formulation of docetaxel in a prostate cancer mouse model. Eur J Pharm Sci 41:369–375

    CAS  PubMed  Google Scholar 

  92. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schweigerer L (1994) The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 368:237–239

    CAS  PubMed  Google Scholar 

  93. D'Amato RJ, Lin CM, Flynn E, Folkman J, Hamel E (1994) 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci U S A 91:3964–3968

    PubMed Central  PubMed  Google Scholar 

  94. Attalla H, Makela TP, Adlercreutz H, Andersson LC (1996) 2-Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin. Biochem Biophys Res Commun 228:467–473

    CAS  PubMed  Google Scholar 

  95. Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ (1997) Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 57:81–86

    CAS  PubMed  Google Scholar 

  96. Sweeney C, Liu G, Yiannoutsos C, Kolesar J, Horvath D, Staab MJ, Fife K, Armstrong V, Treston A, Sidor C, Wilding G (2005) A phase II multicenter, randomized, double-blind, safety trial assessing the pharmacokinetics, pharmacodynamics, and efficacy of oral 2-methoxyestradiol capsules in hormone-refractory prostate cancer. Clin Cancer Res 11:6625–6633

    CAS  PubMed  Google Scholar 

  97. Rajkumar SV, Richardson PG, Lacy MQ, Dispenzieri A, Greipp PR, Witzig TE, Schlossman R, Sidor CF, Anderson KC, Gertz MA (2007) Novel therapy with 2-methoxyestradiol for the treatment of relapsed and plateau phase multiple myeloma. Clin Cancer Res 13:6162–6167

    CAS  PubMed  Google Scholar 

  98. Matei D, Schilder J, Sutton G, Perkins S, Breen T, Quon C, Sidor C (2009) Activity of 2 methoxyestradiol (Panzem NCD) in advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis: a Hoosier Oncology Group trial. Gynecol Oncol 115:90–96

    CAS  PubMed  Google Scholar 

  99. Kulke MH, Chan JA, Meyerhardt JA, Zhu AX, Abrams TA, Blaszkowsky LS, Regan E, Sidor C, Fuchs CS (2011) A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol 68:293–300

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Tinley TL, Leal RM, Randall-Hlubek DA, Cessac JW, Wilkens LR, Rao PN, Mooberry SL (2003) Novel 2-methoxyestradiol analogues with antitumor activity. Cancer Res 63:1538–1549

    CAS  PubMed  Google Scholar 

  101. Mooberry SL (2003) New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agent. Curr Opin Oncol 15:425–430

    CAS  PubMed  Google Scholar 

  102. Dahut WL, Lakhani NJ, Gulley JL, Arlen PM, Kohn EC, Kotz H, McNally D, Parr A, Nguyen D, Yang SX, Steinberg SM, Venitz J, Sparreboom A, Figg WD (2006) Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors. Cancer Biol Ther 5:22–27

    CAS  PubMed  Google Scholar 

  103. LaVallee TM, Burke PA, Swartz GM, Hamel E, Agoston GE, Shah J, Suwandi L, Hanson AD, Fogler WE, Sidor CF, Treston AM (2008) Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198. Mol Cancer Ther 7:1472–1482

    CAS  PubMed  Google Scholar 

  104. Snoeks TJ, Mol IM, Que I, Kaijzel EL, Lowik CW (2011) 2-methoxyestradiol analogue ENMD-1198 reduces breast cancer-induced osteolysis and tumor burden both in vitro and in vivo. Mol Cancer Ther 10:874–882

    CAS  PubMed  Google Scholar 

  105. Aneja R, Zhou J, Vangapandu SN, Zhou B, Chandra R, Joshi HC (2006) Drug-resistant T-lymphoid tumors undergo apoptosis selectively in response to an antimicrotubule agent, EM011. Blood 107:2486–2492

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Aneja R, Kalia V, Ahmed R, Joshi HC (2007) Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection. Mol Cancer Ther 6:2891–2899

    CAS  PubMed  Google Scholar 

  107. Aneja R, Asress S, Dhiman N, Awasthi A, Rida PC, Arora SK, Zhou J, Glass JD, Joshi HC (2010) Non-toxic melanoma therapy by a novel tubulin-binding agent. Int J Cancer 126:256–265

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Karna P, Rida PC, Turaga RC, Gao J, Gupta M, Fritz A, Werner E, Yates C, Zhou J, Aneja R (2012) A novel microtubule-modulating agent EM011 inhibits angiogenesis by repressing the HIF-1alpha axis and disrupting cell polarity and migration. Carcinogenesis 33:1769–1781

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Cheng YC, Liou JP, Kuo CC, Lai WY, Shih KH, Chang CY, Pan WY, Tseng JT, Chang JY (2013) MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1alpha mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR. Mol Cancer Ther 12:1202–1212

    CAS  PubMed  Google Scholar 

  110. Risinger AL, Westbrook CD, Encinas A, Mulbaier M, Schultes CM, Wawro S, Lewis JD, Janssen B, Giles FJ, Mooberry SL (2011) ELR510444, a novel microtubule disruptor with multiple mechanisms of action. J Pharmacol Exp Ther 336:652–660

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Carew JS, Esquivel JA 2nd, Espitia CM, Schultes CM, Mulbaier M, Lewis JD, Janssen B, Giles FJ, Nawrocki ST (2012) ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma. PLoS One 7:e31120

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Burns CJ, Fantino E, Phillips ID, Su S, Harte MF, Bukczynska PE, Frazzetto M, Joffe M, Kruszelnicki I, Wang B, Wang Y, Wilson N, Dilley RJ, Wan SS, Charman SA, Shackleford DM, Fida R, Malcontenti-Wilson C, Wilks AF (2009) CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo. Mol Cancer Ther 8:3036–3045

    CAS  PubMed  Google Scholar 

  113. Lickliter JD, Francesconi AB, Smith G, Burge M, Coulthard A, Rose S, Griffin M, Milne R, McCarron J, Yeadon T, Wilks A, Cubitt A, Wyld DK, Vasey PA (2010) Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent. Br J Cancer 103:597–606

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Burns CJ, Fantino E, Powell AK, Shnyder SD, Cooper PA, Nelson S, Christophi C, Malcontenti-Wilson C, Dubljevic V, Harte MF, Joffe M, Phillips ID, Segal D, Wilks AF, Smith GD (2011) The microtubule depolymerizing agent CYT997 causes extensive ablation of tumor vasculature in vivo. J Pharmacol Exp Ther 339:799–806

    CAS  PubMed  Google Scholar 

  115. Burge M, Francesconi AB, Kotasek D, Fida R, Smith G, Wilks A, Vasey PA, Lickliter JD (2013) Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent. Invest New Drugs 31:126–135

    CAS  PubMed  Google Scholar 

  116. Kremmidiotis G, Leske AF, Lavranos TC, Beaumont D, Gasic J, Hall A, O'Callaghan M, Matthews CA, Flynn B (2010) BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy. Mol Cancer Ther 9:1562–1573

    CAS  PubMed  Google Scholar 

  117. Flynn BL, Gill GS, Grobelny DW, Chaplin JH, Paul D, Leske AF, Lavranos TC, Chalmers DK, Charman SA, Kostewicz E, Shackleford DM, Morizzi J, Hamel E, Jung MK, Kremmidiotis G (2011) Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties. J Med Chem 54:6014–6027

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Rischin D, Bibby DC, Chong G, Kremmidiotis G, Leske AF, Matthews CA, Wong SS, Rosen MA, Desai J (2011) Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation. Clin Cancer Res 17:5152–5160

    CAS  PubMed  Google Scholar 

  119. Garber K (2004) Improved Paclitaxel formulation hints at new chemotherapy approach. J Natl Cancer Inst 96:90–91

    PubMed  Google Scholar 

  120. Montana M, Ducros C, Verhaeghe P, Terme T, Vanelle P, Rathelot P (2011) Albumin-bound paclitaxel: the benefit of this new formulation in the treatment of various cancers. J Chemother 23:59–66

    CAS  PubMed  Google Scholar 

  121. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–1703

    Google Scholar 

  122. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O’Shaughnessy J (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794–7803

    CAS  PubMed  Google Scholar 

  123. Moes J, Koolen S, Huitema A, Schellens J, Beijnen J, Nuijen B (2013) Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. Eur J Pharm Biopharm 83:87–94

    CAS  PubMed  Google Scholar 

  124. Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res 9:2335–2341

    CAS  PubMed  Google Scholar 

  125. Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U, Berghaus A, Dellian M (2008) Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res 14:4603–4611

    CAS  PubMed  Google Scholar 

  126. Eichhorn ME, Ischenko I, Luedemann S, Strieth S, Papyan A, Werner A, Bohnenkamp H, Guenzi E, Preissler G, Michaelis U, Jauch KW, Bruns CJ, Dellian M (2010) Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer. Int J Cancer 126:1235–1245

    CAS  PubMed  Google Scholar 

  127. Lohr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, Folsch UR, Jager D, Osinsky D, Prausova J, Schmidt WE, Lutz MP (2012) Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol 23:1214–1222

    CAS  PubMed  Google Scholar 

  128. Strieth S, Dunau C, Michaelis U, Jager L, Gellrich D, Wollenberg B, Dellian M (2013) Phase I/II clinical study on safety and antivascular effects of paclitaxel encapsulated in cationic liposomes for targeted therapy in advanced head and neck cancer. Head Neck 36:976–984

    Google Scholar 

  129. Wang X, Wang Y, Chen X, Wang J, Zhang X, Zhang Q (2009) NGR-modified micelles enhance their interaction with CD13-overexpressing tumor and endothelial cells. J Control Release 139:56–62

    CAS  PubMed  Google Scholar 

  130. Huang Y, Chen XM, Zhao BX, Ke XY, Zhao BJ, Zhao X, Wang Y, Zhang X, Zhang Q (2010) Antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX): in vitro and in vivo. AAPS PharmSciTech 11:752–759

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Luo LM, Huang Y, Zhao BX, Zhao X, Duan Y, Du R, Yu KF, Song P, Zhao Y, Zhang X, Zhang Q (2013) Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel. Biomaterials 34:1102–1114

    CAS  PubMed  Google Scholar 

  132. Wickstrom M, Larsson R, Nygren P, Gullbo J (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501–508

    PubMed  Google Scholar 

  133. Yu DH, Lu Q, Xie J, Fang C, Chen HZ (2010) Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature. Biomaterials 31:2278–2292

    CAS  PubMed  Google Scholar 

  134. Lee SJ, Ghosh SC, Han HD, Stone RL, Bottsford-Miller J, de Shen Y, Auzenne EJ, Lopez-Araujo A, Lu C, Nishimura M, Pecot CV, Zand B, Thanapprapasr D, Jennings NB, Kang Y, Huang J, Hu W, Klostergaard J, Sood AK (2012) Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma. Clin Cancer Res 18:4114–4121

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, Richie JP, Langer R (2006) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A 103:6315–6320

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Chandran SS, Banerjee SR, Mease RC, Pomper MG, Denmeade SR (2008) Characterization of a targeted nanoparticle functionalized with a urea-based inhibitor of prostate-specific membrane antigen (PSMA). Cancer Biol Ther 7:974–982

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Harrison MR, Hahn NM, Pili R, Oh WK, Hammers H, Sweeney C, Kim K, Perlman S, Arnott J, Sidor C, Wilding G, Liu G (2011) A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal(R) dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC). Invest New Drugs 29:1465–1474

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Bruce JY, Eickhoff J, Pili R, Logan T, Carducci M, Arnott J, Treston A, Wilding G, Liu G (2012) A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate. Invest New Drugs 30:794–802

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Browder T, Butterfield CE, Kräling 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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Tumour Biology and Targeting Program, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, 81, Randwick, NSW, 2031, Australia

    Eddy Pasquier & Maria Kavallaris

  2. Metronomics Global Health Initiative, Marseille, France

    Eddy Pasquier & Nicolas Andre

  3. Australian Centre for Nanomedicine, University of New South Wales, Sydney, NSW, Australia

    Maria Kavallaris

  4. Hematology and Pediatric Oncology Department, La Timone University Hospital of Marseille, Marseille, France

    Nicolas Andre

  5. Faculty of Pharmacy, INSERM UMR 911, Centre de Recherche en Oncologic biologique et en Oncopharmacologie, Aix-Marseille University, Marseille, France

    Nicolas Andre

Authors
  1. Eddy Pasquier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Kavallaris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Andre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eddy Pasquier .

Editor information

Editors and Affiliations

  1. Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Guido Bocci

  2. Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA

    Giulio Francia

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Pasquier, E., Kavallaris, M., Andre, N. (2014). Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments. In: Bocci, G., Francia, G. (eds) Metronomic Chemotherapy. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-43604-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation