Cancer and Metastasis Reviews

, Volume 20, Issue 1–2, pp 79–86

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

  • Robert S. Kerbel
  • Joanne Yu
  • Jennifer Tran
  • Shan Man
  • Alicia Viloria-Petit
  • Giannoula Klement
  • Brenda L. Coomber
  • Janusz Rak


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 


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Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Robert S. Kerbel
    • 1
  • Joanne Yu
    • 1
  • Jennifer Tran
    • 1
  • Shan Man
    • 1
  • Alicia Viloria-Petit
    • 1
  • Giannoula Klement
    • 1
  • Brenda L. Coomber
    • 2
  • Janusz Rak
    • 3
  1. 1.Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences CentreUniversity of TorontoToronto
  2. 2.Biomedical Sciences, Ontario Veterinary CollegeUniversity of GuelphGuelph
  3. 3.Hamilton Civic Hospitals Research CentreMcMaster UniversityHamiltonCanada

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