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AT-A-GLANCE

AT-A-GLANCE

  • “Direct” antiangiogenic agents act directly on untransformed endothelial cells to prevent proliferation, migration, and survival.

  • “Indirect” antiangiogenic agents inhibit tumor-produced oncogene proteins that promote a proangiogenic state.

  • Antiangiogenic agents are a promising class of drugs because they are effective against slow-growing tumors.

In 1971, Judah Folkman published a landmark paper hypothesizing that all tumor growth is dependent on angiogenesis and that inhibitors of angiogenesis could be used to treat cancers.1 The ensuing years have proven him correct and have seen the development of new agents that, either alone or in adjunct, have shown promise not only in oncology but in a variety of dermatologic conditions as well.2

Antiangiogenic drugs can be classified as either “direct” or “indirect;” the direct act directly on untransformed endothelial cells to prevent proliferation, migration, or survival, a process that normally occurs upon stimulation by proangiogenic molecules; the indirect act indirectly by inhibition of tumor-produced oncogenic protein products that promote proangiogenic states. Angiogenesis inhibitors as a drug class provide a unique approach to cancer treatment because they are also effective against slow-growing tumors, whereas traditional therapies, such as chemotherapy and radiation, work best on rapidly-dividing cells. In the future, the switch to an angiogenic phenotype may be able to be blocked in clinically undetectable cancers, thereby preventing disease progression using therapies directed, in part, by angiogenesis biomarkers.3,4 Although application of these agents center so far on oncologic and ophthalmologic diseases, promising and new dermatologic indications are sure to come.2

Figure 195-1 better illustrates the mechanisms of action of some of the drugs described in this chapter, helping to elucidate how they work as antiangiogenic agents.

Figure 195-1

Points of action of some of the antiangiogenic drugs. Schematic depiction of the key points of action of some of the antiangiogenic drugs discussed in this chapter in normal skin, precancerous lesions, and malignancy. bFGF, basic fibroblast growth factor; COX-2, cyclooxygenase 2; CRH, corticotropin-releasing hormone; HIF, histoplasma inhibitory factor; IFN, interferon; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; NF-κB, nuclear factor κB; TIMP, tissue inhibitor of metalloproteinases; Tsp-1, thrombospondin 1; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor 2.

BECAPLERMIN (REGRANEX)

With the rise in incidence of diabetes and the increasingly aging population, chronic wounds have become increasingly prevalent. Treatment of these wounds is particularly challenging because normal wound-healing processes have been disrupted.2

MECHANISM OF ACTION

Becaplermin (recombinant human platelet-derived growth factor BB) is the first FDA-approved angiogenesis-stimulating therapy. Endogenous platelet-derived growth factor (PDGF) is chemotactic for several cell types necessary for wound healing, and is also a mitogen for fibroblasts, the source for extracellular matrix components like glycosaminoglycans and fibronectin. Thus, PDGF is an important factor in the ...

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