Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies

Abstract

Targeting angiogenesis represents a new strategy for the development of anticancer therapies. New targets derived from proliferating endothelial cells may be useful in developing anticancer drugs that prolong or stabilize the progression of tumors with minimal systemic toxicities. These drugs may also be used as novel imaging and radiommunotherapeutic agents in cancer therapy. In this review, the mechanisms and control of angiogenesis are discussed. Genetic and proteomic approaches to defining new potential targets on tumor vasculature are then summarized, followed by discussion of possible antiangiogenic treatments that may be derived from these targets and current clinical trials. Such strategies involve the use of endogenous antiangiogenic agents, chemotherapy, gene therapy, antiangiogenic radioligands, immunotherapy, and endothelial cell-based therapies. The potential biologic end points, toxicities, and resistance mechanisms to antiangiogenic agents must be considered as these therapies enter clinical trials.

Angiostatin's molecular mechanism: Aspects of specificity and regulation elucidated

“…Hypoxia is a major contributor to tumor acidity and also activates the hypoxia-inducible factor, HIF-1a. This transcription factor also regulates pro-angiogenic cytokines [Scappaticci, 2002] and promotes expression of genes involved in metastasis [Semenza, 2003].…”

Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

“…One million tumor cells were injected intradermally into the flanks of each 6-week-old female athymic nude mouse (n ϭ 5). The smallest and largest diameters of the tumors were measured after a 5-day interval using a pair of digital calipers, and the tumor volumes were calculated using the following formula: volume (mm 3 …”

“…1,2 Tumor vessels are genetically stable, and less likely to accumulate mutations that allow them to develop drug resistance in a rapid manner. 3 Therefore, targeting vasculatures that support tumor growth, rather than cancer cells, is considered the most promising approach to cancer therapy.…”

Novel therapies for myelodysplastic syndromes

“…Angiogenesis has emerged as a key biologic process, the dysregulation of which has been established as a prognostic factor not only in patients with solid tumors but also in patients with hematologic malignancies. 71,72 Abnormal secretion of several angiogenic cytokines and growth factors has been demonstrated in vitro by AML blasts. Increased microvessel density, the pathologic correlate for solid tumor vascularization in leukemias, has been shown in MDS bone marrow samples.…”