Lipid messengers as targets for antiangiogenic therapy

Cancer, only second to heart disease, is a leading cause of death in the United States. Despite many years of cancer research little progress has been made in the treatment of many types of cancer. With the advent of molecular biology and advanced biochemical techniques, we have begun to elucidate the various signaling pathways that account for the transformation of normal cells to malignant cells. Our understanding of cancer cell signaling and cell cycle deregulation has paved the way for the rational design of specific inhibitors. Alas, attempts to specifically and exclusively target treatment to the cancer cell have fallen short of expectations for cure and often result in unfortunate drug side effects. More recently, Folkman proposed neovascularization requirements for tumor expansion and metastasis, and this sparked great interest in both the molecular mechanism of tumor-induced angiogenesis and its potential target for anticancer treatment. In this review, we first describe protein growth factors that have been shown to induce endothelial cell proliferation and angiogenesis. We also discuss the signal transduction cascades that result from growth factor receptor binding in light of drugs that are know to inhibit these cascades. Finally, we discuss the potential use of antagonists of lipid second messengers. In particular BN-50730, a PAF antagonist shows promise in preliminary anti-tumor therapy in vitro and in vivo in athymic nude mice by specifically inhibiting angiogenesis.