Antiangiogenesis therapy: an update after the first decade

Angiogenesis is a complex biological phenomenon that forms new blood vessels from the pre-existing vasculature. Aberrant angiogenesis has been implicated in a variety of diseases such as cancer, atherosclerosis, arthritis, obesity, pulmonary hypertension, diabetic retinopathy, and age-related macular degeneration. These conditions collectively affect nearly 10% of the global population. Much effort has focused on identifying new therapeutic agents that inhibit pathological angiogenesis since 1971, when Judah Folkman published the hypothesis that tumor growth is angiogenesis-dependent and that its inhibition may be therapeutic. In 2004, the U.S. Food and Drug Administration approved the first antiangiogenic drug for the treatment of metastatic colon cancer, bevacizumab (Avastin, Genentech). This drug is a humanized monoclonal antibody that neutralizes the vascular endothelial growth factor. It is used in combination with chemotherapy, and its use began the era of antiangiogenesis therapy. Several new therapeutic agents have been added to the list of approved drugs, and clinical trials of new therapeutic options and antiangiogenic agents are ongoing. This review describes the progress made in the first decade of antiangiogenesis therapy, and addresses both validated and possible targets for future drug development.

The discovery of placenta growth factor and its biological activity

Angiogenesis is a complex biological phenomenon crucial for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process confined to the uterus and ovary during the different phases of the menstrual cycle and to the heart and skeletal muscles after prolonged and sustained physical exercise. Conversly, angiogenesis is one of the major pathological changes associated with several complex diseases like cancer, atherosclerosis, arthritis, diabetic retinopathy and age-related macular degeneration. Among the several molecular players involved in angiogenesis, some members of VEGF family, VEGF-A, VEGF-B and placenta growth factor (PlGF), and the related receptors VEGF receptor 1 (VEGFR-1, also known as Flt-1) and VEGF receptor 2 (VEGFR-2, also known as Flk-1 in mice and KDR in human) have a decisive role. In this review, we describe the discovery and molecular characteristics of PlGF, and discuss the biological role of this growth factor in physiological and pathological conditions.