Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias

Leukemia volume 16, pages 376–381 (2002)Cite this article

Abstract

Angiogenesis is essential for growth and metastasis of solid tumors and probably also for hematological malignancies. Angiogenic inhibitors, like endostatin (ES) and PI-88, retard cancer growth. We tested these in mice with juvenile myelomonocytic leukemia (JMML), and in rats with acute myeloid leukemia (BNML). Eight weeks after transplantation and with a continuous drug treatment for the last 4 weeks, the leukemic cell mass decreased from almost 90% of all bone marrow cells to about 15 and 45% with ES, to about 35 and 55% with PI-88, and to about 10 and 25% with ES + PI-88 in the leukemic mice and rats, respectively. The numbers of normal human bone marrow cells transplanted into mice were unchanged by the treatments. The microvessel density in leukemic animals given ES or PI-88 was 10–50% of that in untreated animals. Notably, simultaneous treatment with ES and PI-88 led to a reduction of about 95% in JMML mice and 85% in BNML rats. In vitro proliferation of either JMML or BNML cells was not significantly altered by either drug, demonstrating the selectivity of ES and PI-88 as angiogenic inhibitors. In conclusion, anti-angiogenic therapy may be a valuable adjunct to conventional treatment of leukemia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell 1996 86: 353–364

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D . Signaling vascular morphogenesis and maintenance Science 1997 277: 48–50

    Article  CAS  PubMed  Google Scholar 

  3. Bergers G, Javaherian K, Lo K-M, Folkman J, Hanahan D . Effects of angiogenesis inhibitors on multistage carcinogenesis in mice Science 1999 284: 808–812

    Article  CAS  PubMed  Google Scholar 

  4. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J . Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia Am J Pathol 1997 150: 815–821

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hussong JW, Rodgers GM, Shami PJ . Evidence of increased angiogenesis in patients with acute myeloid leukemia Blood 2000 95: 309–313

    CAS  PubMed  Google Scholar 

  6. Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, Giles F, Estrov Z, Barlogie B, Albitar M . Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia Blood 1999 94: 3717–3721

    CAS  PubMed  Google Scholar 

  7. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J . Endostatin: an endogenous inhibitor of angiogenesis and tumor growth Cell 1997 88: 277–285

    Article  CAS  PubMed  Google Scholar 

  8. Parish CR, Freeman C, Brown KJ, Francis DJ, Cowden WB . Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity Cancer Res 1999 59: 3433–3441

    CAS  PubMed  Google Scholar 

  9. Arico M, Biondi A, Pui CH . Juvenile myelomonocytic leukemia Blood 1997 90: 479–488

    CAS  PubMed  Google Scholar 

  10. Matthes-Martin S, Mann G, Peters C, Lion T, Fritsch G, Haas OA, Potschger U, Gadner H . Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature Bone Marrow Transplant 2000 26: 377–382

    Article  CAS  PubMed  Google Scholar 

  11. Iversen PO, Lewis ID, Turczynowicz S, Hasle H, Niemeyer C, Schmiegelow K, Bastiras S, Biondi A, Hughes TP, Lopez AF . Inhibition of granulocyte–macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice Blood 1997 90: 4910–4917

    CAS  PubMed  Google Scholar 

  12. Bruserud Ø, Tjønnfjord G, Gjertsen BT, Foss B, Ernst P . New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients Stem Cells 2000 18: 343–351

    CAS  PubMed  Google Scholar 

  13. van Bekkum DW, Hagenbeek A . Relevance of the BN leukemia as a model for human acute myeloid leukemia Blood Cells 1977 3: 565–579

    Google Scholar 

  14. Martens ACM, van Bekkum DW, Hagenbeek A . The BN acute myelocytic leukemia (BNML) Leukemia 1990 4: 241–257

    CAS  PubMed  Google Scholar 

  15. Skrede S, Iversen PO . Enhanced oxygen consumption and fatty acid metabolism in rat bone marrow with acute promyelocytic leukaemia Leuk Res 1995 19: 463–467

    Article  CAS  PubMed  Google Scholar 

  16. Mortensen BT, Jensen PO, Helledie N, Iversen PO, Ralfkiær E, Larsen JK, Madsen MT . Changing bone marrow microenvironment during development of acute myeloid leukaemia in rats Br J Haematol 1998 102: 458–464

    Article  CAS  PubMed  Google Scholar 

  17. Jensen PØ, Mortensen BT, Hodgkiss RJ, Iversen PO, Christensen IJ, Helledie N, Larsen JK . Increased cellular hypoxia and reduced proliferation of both normal and leukaemic cells during progression of acute myeloid leukemia in rats Cell Prolif 2000 33: 381–395

    Article  CAS  PubMed  Google Scholar 

  18. Iversen PO, Rodwell RL, Pitcher L, Taylor KM, Lopez AF . Inhibition of proliferation and induction of apoptosis in juvenilemyelomonocytic leukemic cells by the granulocyte–macrophagecolony-stimulating factor analogue E21R Blood 1996 88: 2634–2639

    CAS  PubMed  Google Scholar 

  19. Sim BKL, Fogler WF, Zhou XH, Liang H, Madsen JW, Luu K, O'Reilly MS, Tomaszewsky JE, Fortier AH . Zinc ligand-disrupted recombinant human endostatin: potent inhibition of tumor growth, safety and pharmacokinetic profile Angiogenesis 1999 3: 41–51

    Article  CAS  PubMed  Google Scholar 

  20. Martens AC, Johnson RJ, Kaizer H, Hagenbeek A . Characteristics of a monoclonal antibody (RM124) against acute myelocytic leukemia cells Exp Hematol 1984 12: 667–671

    CAS  PubMed  Google Scholar 

  21. Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engstrøm A, Timpl R, Welsh M, Claesson-Welsh L . Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis Blood 2000 95: 3403–3411

    CAS  PubMed  Google Scholar 

  22. Freedman MH, Cohen A, Grunberger T, Bunin N, Luddy RE, Saunders EF, Shahidi N, Lau A, Estrov Z . Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia Br J Haematol 1992 80: 40–48

    Article  CAS  PubMed  Google Scholar 

  23. Hagenbeek A, Martens ACM . High-dose cyclophosphamide treatment of acute myelocytic leukemia. Studies in the BNML rat model Eur J Cancer Clin Oncol 1982 18: 763–769

    Article  CAS  PubMed  Google Scholar 

  24. Padro T, Ruiz S, Bieker R, Burger H, Steins M, Kienast J, Buchner T, Berdel WE, Mesters RM . Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia Blood 2000 95: 2637–2644

    CAS  PubMed  Google Scholar 

  25. Musso O, Rehn M, Theret N, Turlin B, Bioulac-Sage P, Lotrian D, Campion JP, Pihlajaniemi T, Clement B . Tumor progression is associated with a significant decrease in the expression of the endostatin precursor collagen XVIII in human hepatocellular carcinomas Cancer Res 2001 61: 45–49

    CAS  PubMed  Google Scholar 

  26. Ratel D, Nasser V, Dupre I, Benabid AL, Berger F . Antibodies to endostatin in a multifocal glioblastoma patient Lancet 2000 356: 1656–1657

    Article  CAS  PubMed  Google Scholar 

  27. Kim Y-M, Jang J-W, Lee O-H, Yeon J, Choi EY, Kim KW, Lee ST, Kwon YG . Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase 2 Cancer Res 2000 60: 5410–5413

    CAS  PubMed  Google Scholar 

  28. Yamaguchi N, Anand-Apte B, Lee M . Sasaki T, Fukai N, Shapiro R, Que I, Lowick C, Timpl R, Olsen BR. Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding EMBO J 1999 18: 4414–4423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carmeliet P, Jain RK . Angiogenesis in cancer and other diseases Nature 2000 407: 249–257

    Article  CAS  PubMed  Google Scholar 

  30. Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S . The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing FASEB J 2000 14: 2373–2376

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was financed by The Norwegian Cancer Society, The Norwegian Research Council, and The Throne Holst Foundation. We thank BKL Sim for the generous supply of endostatin, and CR Parish and DM Podger for kindly providing PI-88. The RM124 antibody was a kind gift from JK Larsen.

Author information

Authors and Affiliations

  1. Institute for Nutrition Research, University of Oslo, Oslo, Norway

    PO Iversen

  2. Department of Comparative Medicine, The National Hospital, Oslo, Norway

    DR Sorensen

  3. Department of Physiology, University of Oslo, Oslo, Norway

    HB Benestad

Authors
  1. PO Iversen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. DR Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. HB Benestad
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iversen, P., Sorensen, D. & Benestad, H. Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia 16, 376–381 (2002). https://doi.org/10.1038/sj.leu.2402376

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402376

Keywords

This article is cited by

Search

Advanced search

Quick links