Angiogenesis in the development of head and neck cancer and its inhibitionby chemopreventive agents

Squamous cell carcinoma is an aggressive malignancy that often develops as multiple independent lesions throughout the mucosa of the upper aerodigesti ve tract. Therefore, the comprehensive treatment of this disease must not o nly address the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surf aces. The need to treat these lesions has resulted in a search for chemopre ventive agents that can halt or even reverse their malignant progression. T he biologic and molecular mechanisms by which most chemopreventive agents a ct have remained unclear and controversial Recent work from several laborat ories has demonstrated that some drugs may act in part by inhibiting the ab ility of tumors to induce blood vessel growth. Angiogenesis, the growth of new blood vessel from preexisting ones, is absolutely required for solid ne oplasms to grow beyond 2-3 mm in diameter. Therefore, chemopreventive agent s 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 t umor cells that result in the switch from an anti-angiogenic to an angiogen ic phenotype. Ln addition, it will discuss the mechanisms by which some che mopreventive agents, presently under clinical investigation, inhibit tumor angiogenesis. Finally, this paper will present a rationale for the use of m ultiple anti-angiogenic agents as a means of developing new chemopreventive protocols that result in reduced patient toxicity while maintaining simila r clinical efficacies.