Cancer and Metastasis Reviews

, Volume 20, Issue 1, pp 79–86

Possible Mechanisms of Acquired Resistance to Anti-angiogenic Drugs: Implications for the Use of Combination Therapy Approaches

Authors

  • Robert S. Kerbel
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Joanne Yu
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Jennifer Tran
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Shan Man
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Alicia Viloria-Petit
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Giannoula Klement
    • Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of Toronto
  • Brenda L. Coomber
    • Biomedical Sciences, Ontario Veterinary CollegeUniversity of Guelph
  • Janusz Rak
    • Hamilton Civic Hospitals Research CentreMcMaster University
Article

DOI: 10.1023/A:1013172910858

Cite this article as:
Kerbel, R.S., Yu, J., Tran, J. et al. Cancer Metastasis Rev (2001) 20: 79. doi:10.1023/A:1013172910858

Abstract

The ultimate target of anti-angiogenic drugs is the genetically stable, activated endothelial cell of a newly forming tumor blood vessel, rather than the genetically unstable tumor cell population per se. This led to the notion that acquired resistance to such drugs may not develop as readily, if at all. While there is some evidence that this lack of resistance development may be the case for some direct-acting angiogenesis inhibitors, it is becoming apparent that resistance can develop over time to many types of angiogenesis inhibitors including, possibly, some direct inhibitors, especially when used as monotherapies. Possible mechanisms for such acquired or induced resistance include: (i) redundancy of pro-angiogenic growth factors when the drug used targets a single such growth factor or its cognate endothelial cell-associated receptor tyrosine kinase; (ii) the anti-apoptotic/pro-survival function of growth factors such as VEGF, which, in high local concentrations, can antagonize the pro-apoptotic effects of various angiogenesis inhibitors; (iii) epigenetic, transient upregulation, or induction, of various anti-apoptotic effector molecules in host-endothelial cells; and (iv) heterogeneous vascular dependence of tumor cell populations. It is suggested that long-term disease control with anti-angiogenic drugs can be best achieved by judicious combination therapy. In this regard, the great molecular diversity of anti-angiogenic drug targets, in contrast to chemotherapy, makes this a particularly attractive therapeutic option, especially when approved, commercially available drugs considered to have anti-angiogenic effects are used in such combination treatment strategies.

acquired drug resistance anti-angiogenic drugs

Copyright information

© Kluwer Academic Publishers 2001