Copyright © 2012 Una Adamcic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

1. U. Emmenegger, S. Man, Y. Shaked et al., “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 Research, vol. 64, no. 11, pp. 3994–4000, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
2. M. Colleoni, L. Orlando, G. Sanna et al., “Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects,” Annals of Oncology, vol. 17, no. 2, pp. 232–238, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
3. K. Garber, “Could less be more? Low-dose chemotherapy goes on trial,” Journal of the National Cancer Institute, vol. 94, no. 2, pp. 82–84, 2002. View at Scopus
4. T. Browder, C. E. Butterfield, B. M. Kräling et al., “Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer,” Cancer Research, vol. 60, no. 7, pp. 1878–1886, 2000. View at Scopus
5. L. G. Daenen, Y. Shaked, S. Man et al., “Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models,” Molecular Cancer Therapeutics, vol. 8, no. 10, pp. 2872–2881, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
6. Y. Hamano, H. Sugimoto, M. A. Soubasakos et al., “Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression,” Cancer Research, vol. 64, no. 5, pp. 1570–1574, 2004. View at Publisher · View at Google Scholar · View at Scopus
7. G. Bocci, G. Francia, S. Man, J. Lawler, and R. S. Kerbel, “Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 12917–12922, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
8. J. S. De Jong, P. J. Van Diest, P. Van Der Valk, and J. P. A. Baak, “Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: an inventory in search of autocrine and paracrine loops,” Journal of Pathology, vol. 184, no. 1, pp. 44–52, 1998. View at Publisher · View at Google Scholar · View at Scopus
9. G. Gasparini, “Metronomic scheduling: the future of chemotherapy?” The Lancet Oncology, vol. 2, no. 12, pp. 733–740, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
10. G. Klement, S. Baruchel, J. Rak et al., “Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity,” Journal of Clinical Investigation, vol. 105, no. 8, pp. R15–R24, 2000. View at Scopus
11. A. L. Wong, Z. A. Haroon, S. Werner, M. W. Dewhirst, C. S. Greenberg, and K. G. Peters, “Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues,” Circulation Research, vol. 81, no. 4, pp. 567–574, 1997. View at Scopus
12. K. E. Fathers, C. M. Stone, K. Minhas et al., “Heterogeneity of Tie2 expression in tumor microcirculation: influence of cancer type, implantation site, and response to therapy,” The American Journal of Pathology, vol. 167, no. 6, pp. 1753–1762, 2005. View at Scopus
13. M. Hockel and P. Vaupel, “Biological consequences of tumor hypoxia,” Seminars in Oncology, vol. 28, pp. 36–41, 2001.
14. P. Vaupel, D. K. Kelleher, and M. Hockel, “Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy,” Seminars in Oncology, vol. 28, pp. 29–35, 2001.
15. R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?” Nature Reviews Cancer, vol. 4, no. 11, pp. 891–899, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
16. A. Das, W. Fanslow, D. Cerretti, E. Warren, N. Talarico, and P. McGuire, “Angiopoietin/Tek interactions regulate mmp-9 expression and retinal neovascularization,” Laboratory Investigation, vol. 83, no. 11, pp. 1637–1645, 2003. View at Publisher · View at Google Scholar · View at Scopus
17. J. Folkman, “Angiogenesis,” Annual Review of Medicine, vol. 57, pp. 1–18, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
18. R. S. Bhatt, J. Merchan, R. Parker et al., “A phase 2 pilot trial of low-dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma,” Cancer, vol. 116, no. 7, pp. 1751–1756, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
19. D. G. Perez, V. J. Suman, T. R. Fitch et al., “Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A,” Cancer, vol. 115, no. 1, pp. 119–127, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
20. K. A. Varker, J. E. Biber, C. Kefauver et al., “A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma,” Annals of Surgical Oncology, vol. 14, no. 8, pp. 2367–2376, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
21. J. L. Brown, Z. A. Cao, M. Pinzon-Ortiz et al., “A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models,” Molecular Cancer Therapeutics, vol. 9, no. 1, pp. 145–156, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
22. S. Dellapasqua, F. Bertolini, V. Bagnardi et al., “Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer,” Journal of Clinical Oncology, vol. 26, no. 30, pp. 4899–4905, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
23. U. Rodeck, M. Herlyn, H. D. Menssen, R. W. Furlanetto, and H. Koprowski, “Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors,” International Journal of Cancer, vol. 40, no. 5, pp. 687–690, 1987. View at Scopus
24. P. Mombaerts, J. Iacomini, R. S. Johnson, K. Herrup, S. Tonegawa, and V. E. Papaioannou, “RAG-1-deficient mice have no mature B and T lymphocytes,” Cell, vol. 68, no. 5, pp. 869–877, 1992. View at Publisher · View at Google Scholar · View at Scopus
25. G. J. Guillemin and B. J. Brew, “Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification,” Journal of Leukocyte Biology, vol. 75, no. 3, pp. 388–397, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
26. E. M. Bridges and A. L. Harris, “The angiogenic process as a therapeutic target in cancer,” Biochemical Pharmacology, vol. 81, pp. 1183–1191, 2011.
27. M. I. Lin and W. C. Sessa, “Antiangiogenic therapy: creating a unique “window” of opportunity,” Cancer Cell, vol. 6, no. 6, pp. 529–531, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
28. P. Carmeliet and R. K. Jain, “Angiogenesis in cancer and other diseases,” Nature, vol. 407, no. 6801, pp. 249–257, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
29. S. B. Coffelt, C. E. Lewis, L. Naldini, J. M. Brown, N. Ferrara, and M. De Palma, “Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors,” The American Journal of Pathology, vol. 176, no. 4, pp. 1564–1576, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
30. M. Hangai, Y. S. Moon, N. Kitaya et al., “Systemically expressed soluble Tie2 inhibits intraocular neovascularization,” Human Gene Therapy, vol. 12, no. 10, pp. 1311–1321, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
31. P. Lin, P. Polverini, M. Dewhirst, S. Shan, P. S. Rao, and K. Peters, “Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth,” Journal of Clinical Investigation, vol. 100, no. 8, pp. 2072–2078, 1997. View at Scopus
32. K. G. Peters, C. D. Kontos, P. C. Lin et al., “Functional significance of Tie2 signaling in the adult vasculature,” Recent Progress in Hormone Research, vol. 59, pp. 51–71, 2004. View at Publisher · View at Google Scholar · View at Scopus
33. P. Lin, J. A. Buxton, A. Acheson et al., “Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 15, pp. 8829–8834, 1998. View at Publisher · View at Google Scholar · View at Scopus
34. G. Siemeister, M. Schirner, K. Weindel et al., “Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway,” Cancer Research, vol. 59, no. 13, pp. 3185–3191, 1999. View at Scopus
35. A. Stratmann, T. Acker, A. M. Burger, K. Amann, W. Risau, and K. H. Plate, “Differential inhibition of tumor angiogenesis by tie2 and vascular endothelial growth factor receptor-2 dominant-negative receptor mutants,” International Journal of Cancer, vol. 91, no. 3, pp. 273–282, 2001. View at Publisher · View at Google Scholar · View at Scopus
36. S. Tanaka, K. Sugimachi, Y. I. Yamashita et al., “Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma,” Hepatology, vol. 35, no. 4, pp. 861–867, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
37. F. Bertolini, S. Paul, P. Mancuso et al., “Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells,” Cancer Research, vol. 63, no. 15, pp. 4342–4346, 2003. View at Scopus
38. J. L. Yu, J. W. Rak, P. Carmeliet, A. Nagy, R. S. Kerbel, and B. L. Coomber, “Heterogeneous vascular dependence of tumor cell populations,” The American Journal of Pathology, vol. 158, no. 4, pp. 1325–1334, 2001. View at Scopus
39. P. V. Dickson, J. B. Hamner, T. L. Sims et al., “Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy,” Clinical Cancer Research, vol. 13, no. 13, pp. 3942–3950, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
40. S. Song, A. J. Ewald, W. Stallcup, Z. Werb, and G. Bergers, “PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival,” Nature Cell Biology, vol. 7, no. 9, pp. 870–879, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
41. Y. Hasumi, A. Klosowska-Wardega, M. Furuhashi, A. Östman, C. H. Heldin, and C. Hellberg, “Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling,” International Journal of Cancer, vol. 121, no. 12, pp. 2606–2614, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
42. R. Harfouche and S. N. A. Hussain, “Signaling and regulation of endothelial cell survival by angiopoietin-2,” The American Journal of Physiology, vol. 291, no. 4, pp. H1635–H1645, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
43. I. B. Lobov, P. C. Brooks, and R. A. Lang, “Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 17, pp. 11205–11210, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
44. K. Teichert-Kuliszewska, P. C. Maisonpierre, N. Jones et al., “Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2,” Cardiovascular Research, vol. 49, no. 3, pp. 659–670, 2001. View at Publisher · View at Google Scholar · View at Scopus
45. P. C. Maisonpierre, C. Suri, P. F. Jones et al., “Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis,” Science, vol. 277, no. 5322, pp. 55–60, 1997. View at Publisher · View at Google Scholar · View at Scopus
46. L. Eklund and B. R. Olsen, “Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling,” Experimental Cell Research, vol. 312, no. 5, pp. 630–641, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
47. H. T. Yuan, E. V. Khankin, S. A. Karumanchi, and S. M. Parikh, “Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium,” Molecular and Cellular Biology, vol. 29, no. 8, pp. 2011–2022, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
48. R. S. Kerbel, J. Yu, J. Tran et al., “Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches,” Cancer and Metastasis Reviews, vol. 20, no. 1-2, pp. 79–86, 2001. View at Publisher · View at Google Scholar · View at Scopus
49. G. D. Yancopoulos, S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash, “Vascular-specific growth factors and blood vessel formation,” Nature, vol. 407, no. 6801, pp. 242–248, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
50. J. A. Garcia-Saenz, M. Martin, A. Calles, et al., “Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer,” Journal of Chemotherapy, vol. 20, pp. 632–639, 2008.
51. J. M. Jurado, A. Sanchiz, B. Pajares, E. Perez, L. Alonso, and E. Alba, “Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer,” Clinical and Translational Oncology, vol. 10, pp. 583–586, 2008.
52. O. Casanovas, D. J. Hicklin, G. Bergers, and D. Hanahan, “Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors,” Cancer Cell, vol. 8, no. 4, pp. 299–309, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
53. T. T. Batchelor, A. G. Sorensen, E. Di Tomaso et al., “AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients,” Cancer Cell, vol. 11, no. 1, pp. 83–95, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
54. G. Bocci, S. Man, S. K. Green et al., “Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies,” Cancer Research, vol. 64, no. 18, pp. 6616–6625, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus