Squamous cell carcinoma is an aggressive malignancy that often develops as multiple independent lesions throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this disease must not only address the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surfaces. The need to treat these lesions has resulted in a search for chemopreventive agents that can halt or even reverse their malignant progression. The biologic and molecular mechanisms by which most chemopreventive agents act have remained unclear and controversial. Recent work from several laboratories has demonstrated that some drugs may act in part by inhibiting the ability of tumors to induce blood vessel growth. Angiogenesis, the growth of new blood vessels from pre-existing ones, is absolutely required for solid neoplasms to grow beyond 2-3 mm in diameter. Therefore, chemopreventive agents that act to inhibit angiogenesis may provide a very powerful modality by which one may limit the growth of both premalignant lesions and small nests of tumor cells. This review will outline the basic changes that occur in tumor cells that result in the switch from an anti-angiogenic to an angiogenic phenotype. In addition, it will discuss the mechanisms by which some chemopreventive agents, presently under clinical investigation, inhibit tumor angiogenesis. Finally, this paper will present a rationale for the use of multiple anti-angiogenic agents as a means of developing new chemopreventive protocols that result in reduced patient toxicity while maintaining similar clinical efficacies.
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