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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.
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Antiangiogenic drugs can be classified as either “direct” or “indirect,” the former acting directly on untransformed endothelial cells to prevent proliferation, migration, or survival, a process that normally occurs upon stimulation by proangiogenic molecules; and the latter 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, while 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, thus preventing disease progression using therapies directed, in part, by angiogenesis biomarkers.2,3 Current applications of these agents center on oncologic and ophthalmologic diseases but dermatologic indications are also promising.
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Figure 235-1 shows the key points of action of some of the antiangiogenic drugs discussed in this chapter in normal skin, inflammatory conditions, precancerous lesions, and malignancy.
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(See also Chapters 231 and 234)
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Interferon-α (IFN-α) made history in 1988 as the first antiangiogenic therapy used in humans, for the successful treatment of pulmonary hemangiomatosis in a pediatric patient. IFN-α 2b is a synthetic cytokine made from the bacterium Escherichia coli transformed with recombinant DNA, and has similar actions to its natural endogenous counterpart, IFN-α, a type I IFN produced naturally by the immune system.
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The IFNs act through the Janus kinase-signal transducers and activators of transcription (Jak-STAT) pathway. IFN-α, which is both a direct and indirect antiangiogenic agent, ...