Antiangiogenesis Drug Design: Multiple Pathways Targeting Tumor Vasculature

Abstract

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.

Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor–Dependent Hypoxia-Inducible Factor Stabilization

“…Hypoxia-induced expression of VEGF is a critical step in the malignant progression of tumors and is the target of multiple anticancer modalities (39). To determine whether hypoxia-induced VEGF transcription was similarly attenuated by MIF depletion in pancreatic carcinoma cells, we did real-time PCR analysis on cells with or without MIF that had been exposed to hypoxia for differing times.…”

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

“…Although anti-cancer chemotherapy mainly consists in the use of cytotoxic agents interfering with cell division, another research field has recently emerged with the design and identification of agents able to inhibit or limit the metastatic process. Indeed, many efforts are now focussed on the search of compounds interfering with the cancer cell invasion process and expressing antiangiogenic properties [1]. Examples of drugs, among which monoclonal antibodies and small molecules, are currently under clinical investigation and some of them have recently been approved for use in man in the treatment of several cancers associated or not with conventional chemotherapies or radiation therapies [2][3][4][5][6][7][8][9].…”

“…Examples of drugs, among which monoclonal antibodies and small molecules, are currently under clinical investigation and some of them have recently been approved for use in man in the treatment of several cancers associated or not with conventional chemotherapies or radiation therapies [2][3][4][5][6][7][8][9]. These drugs comprise vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) inhibitors (monoclonal antibodies) as well as VEGF and EGF receptor tyrosine kinase inhibitors (small-molecule inhibitors), but also matrix metalloproteinase (MMP), urokinase (uPA), cycloogygenase-2 (COX-2) or methionine aminopeptidase inhibitors [1].…”

Therapeutic Targeting of Angiogenesis with a Recombinant CTT Peptide–Endostatin Mimic–Kringle 5 Protein

“…The use of multitargeted antiangiogenic agent such as AARP is an appealing approach targeting nonmalignant endothelial cells that form the tumor vasculature and indirectly affects tumor cells, thus minimizing the risk of toxicity (22). A gram of tumor has been estimated to contain approximately 10 8 to 10 9 tumor cells, and the ratio of endothelial cells to tumor cell is in the range of 1/10 to 1/100 (19).…”

“…Antiangiogenic tumor therapies with endogenous inhibitors have attracted intense interest because of their broad spectrum of action, low toxicity, and absence of drug resistance (4,3,21). However, tumor angiogenesis is a complex process resulting from numerous signaling molecules and pathways from the tumor microenvironment, and inhibition of a tumor angiogenesis pathway by a single drug alone is not sufficient to block redundancies in tumor angiogenesis regulators (21,22). Therefore, the development of multitargeted antiangiogenic agent is needed for tackling these challenges and arises as an attractive therapeutic approach to treat cancer and other angiogenesis-dependent diseases (22).…”