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DOI: 10.1080/01926230600611836
Review of the Effects of Anti-Angiogenic Compounds on the Epiphyseal Growth PlateAstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, England Correspondence: Address correspondence to: Anthony Peter Hall, AstraZeneca R&D, Alderley Park, Safety Assessment UK, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, England; e-mail:Peter.a.hall{at}astrazeneca.com The formation of new blood vessels from a pre-existing vascular bed, termed "angiogenesis," is of critical importance for the growth and development of the animal since it is required for the growth of the skeleton during endochondral ossification, development and cycling of the corpus luteum and uterus, and for the repair of tissues during wound healing. "Vasculogenesis," the de novo formation of blood vessels is also important for the proper function and development of the vascular system in the embryo. New blood vessel formation is a prominent feature and permissive factor in the relentless progression of many human diseases, one of the most important examples of which is neoplasia. It is for this reason that angiogenesis is considered to be one of the hallmarks of cancer. The development of new classes of drugs that inhibit the growth and proper functioning of new blood vessels in vivo is likely to provide significant therapeutic benefit in the treatment of cancer, as well as other conditions where angiogenesis is a strong driver to the disease process. During the preclinical safety testing of these drugs, it is becoming increasingly clear that their in vivo efficacy is reflected in the profile of "expected toxicity" (resulting from pharmacology) observed in laboratory animals, so much so, that this profile of "desired" toxicity may act as a signature for their anti-angiogenic effect. In this article we review the major mechanisms controlling angiogenesis and its role during endochondral ossification. We also review the effects of perturbation of endochondral ossification through four mechanisms—inhibition of vascular endothelial growth factor (VEGF), pp60 c-Src kinase and matrix metalloproteinases as well as disruption of the blood supply with vascular targeting agents. Inhibition through each of these mechanisms appears to have broadly similar effects on the epiphyseal growth plate characterised by thickening due to the retention of hypertrophic chondrocytes resulting from the inhibition of angiogenesis. In contrast, in the metaphysis there are differing effects reflecting the specific role of these targets at this site.
Key Words: Review • angiogenesis • epiphyseal growth plate • endochondral ossification • corpus luteum • VEGF • VEGFR • pp60 c-Src kinase inhibitor • matrix metalloproteinase inhibitor • vascular targeting/tubulin binding agent Abbreviations: ADEPT, antibody-directed enzyme prodrug therapy strategy •
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SMA, alpha smooth muscle actin • Ang, angiopoietins • bFGF, basic fibroblast growth factor • D, desmin • EDB, extra domain B • EDG1, endothelial differentiation/sphingolipid G-protein-coupled receptor, 1 • EG-VEGF, endocrine derived vascular endothelial growth factor • FGF, fibroblast growth factor • FGFR, fibroblast growth factor receptor • HIF, hypoxia inducible factor • IFN-
, interferon gamma • JAM-1, junctional adhesion molecule • Mitf, micropthalmia transcription factor • MMP, matrix metalloproteinase • MT1-MMP, membrane type 1 matrix metalloproteinase • MHC II, major histocompatibility class II • PA, plasminogen activator • PAI-1, plasminiogen activator inhibitor I • PDGF-B, platelet derived growth factor-B • PDGFRβ, platelet derived growth factor receptor beta • PECAM-1, platelet/endothelial cell adhesion molecule • PlGF, placental growth factor • S1P1, sphingosine-1-phosphate-1 • TGF-β, transforming growth factor beta • TGF-Rβ, transforming growth factor receptor beta • TIMPs, tissue inhibitor of metalloproteinases • vSMC, vascular smooth muscle cell • VE, vascular endothelial • VEGFR, vascular endothelial growth factor receptor • VEGF, vascular endothelial growth factor • V, vimentin