Antiangiogenesis drug design

Multiple pathways targeting tumor vasculature

Haizhen Andrew Zhong, J. Phillip Bowen

Research output: Contribution to journalReview article

57 Citations (Scopus)

Abstract

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.

Original languageEnglish (US)
Pages (from-to)849-862
Number of pages14
JournalCurrent Medicinal Chemistry
Volume13
Issue number8
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

Fingerprint

Drug Design
Angiogenesis Inhibitors
Blood vessels
Tumors
Blood Vessels
Growth
Pharmaceutical Preparations
Switches
Neoplasms
Pathologic Neovascularization
Vascular Tissue Neoplasms
Thrombospondin 1
Cyclooxygenase 2
Tubulin
Matrix Metalloproteinases
Growth and Development
Chemotherapy
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Nutrients

Keywords

  • Antimitotic agents
  • COX-2
  • Chemotherapy
  • Curcumin
  • MMP-9 deficient mice
  • VEGF isoforms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Antiangiogenesis drug design : Multiple pathways targeting tumor vasculature. / Zhong, Haizhen Andrew; Bowen, J. Phillip.

In: Current Medicinal Chemistry, Vol. 13, No. 8, 01.04.2006, p. 849-862.

Research output: Contribution to journalReview article

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