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Clinical translation of angiogenesis inhibitors

Key Points

  • Angiogenesis inhibitors are a relatively new class of cancer drugs. The biological and biochemical characteristics of angiogenesis inhibitors, however, differ from conventional cytotoxic chemotherapy.

  • Basic research into the angiogenic process has revealed several ways by which the clinical efficacy of angiogenesis inhibitors can be improved. These include:

  • Differentiating between direct and indirect angiogenesis inhibitors.

  • Realizing that the microvascular endothelial cell is a genetically stable target of anti-angiogenic therapy.

  • Understanding that slowly growing tumours, which are more difficult to treat by chemotherapy, respond well to anti-angiogenic therapy.

  • An appreciation that rapidly growing tumours require higher doses of an angiogenesis inhibitor.

  • Angiogenesis inhibitors are most effective when administered on a dose-schedule that maintains a constant concentration in the circulation instead of a schedule in which therapy is periodically discontinued. Chemotherapy seems to be angiogenesis dependent, in part, and a change in schedule to optimally target the endothelial cell instead of the tumour cell can overcome drug resistance in tumour-bearing mice.

  • A current unsolved problem in anti-angiogenic therapy is the lack of surrogate markers for therapeutic efficacy. Whether quantification of circulating progenitor endothelial cells will become an indicator of efficacy remains to be shown.

  • When various angiogenesis inhibitors become available for clinical use in cancer patients, these new therapeutic agents might be added to chemotherapy or to radiotherapy, or used in combination with immunotherapy or vaccine therapy.

Abstract

Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?

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Figure 1: Direct and indirect angiogenesis inhbitors.
Figure 2: Tumour cells form cuffs around functional microvessels in a Dunning rat prostate carcinoma xenograft.

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Acknowledgements

We thank W. Foss and A. Clapp for administrative assistance.

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Cancer.gov

acute lymphoblastic leukaemia

bladder cancer

bone cancer

breast cancer

cervical cancer

Kaposi's sarcoma

lung cancer

melanoma

multiple myeloma

myelodysplastic syndrome

non-Hodgkin's lymphoma

oropharyngeal cancer

pancreatic cancer

prostate cancer

rectal cancer

renal-cell carcinoma

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endoglin

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FLK1

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Ifn-α

IFN-α

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methionine aminopeptidase-2

neuropilin

p53

PAI1

PD-EGF

pleiotrophin

PLGF

Ras

RB

TGF-β

Tnf-α

TNF-α

Trp53

TSP1

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Vegf

VEGF

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cyclophosphamide

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etoposide

5-fluorouracil

ibuprofen

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topotecan

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FURTHER INFORMATION

Angiogenesis inhibitors

Cancer clinical trials

Celgene site on thalidomide

Glossary

SIMIAN VIRUS 40 (SV40) TUMOUR ANTIGEN

A multifunctional phosphoprotein that is synthesized early in SV40 infection. It is required for virus DNA replication and for the regulation of viral gene expression in infected cells, as well as for the induction and maintenance of malignant transformation.

ANOXIA

Complete lack of oxygen in tissues. This is different from hypoxia, which is defined as a low level of oxygen in tissues.

BENCE–JONES PROTEIN

A monoclonal immunoglobulin that is produced by neoplastic plasma cells in patients with multiple myeloma. This protein can be detected in the urine and its concentration correlates directly with tumour volume.

PULMONARY HAEMANGIOMATOSIS

Abnormal excessive growth of capillary blood vessels in the lungs, leading to haemorrhage and heart failure.

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Kerbel, R., Folkman, J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2, 727–739 (2002). https://doi.org/10.1038/nrc905

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