o-(chloroacetylcarbamoyl)fumagillol and marimastat

Topics: Angiostatins; Antibiotics, Antineoplastic; Antineoplastic Agents; Collagen; Cyclohexanes; Endostatins; Humans; Hydroxamic Acids; Interferons; Interleukin-12; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Phenylalanine; Plasminogen; Sesquiterpenes; Thalidomide; Thiophenes

Aberrant angiogenesis is closely involved in invasion/metastasis as well as enlargement of tumor. One recent highlight is to develop anti angiogenic drugs by targeting tumor angiogenesis. Here we describe how tumor angiogenesis is regulated and also recent topics related to angiogenic drug in clinical trials.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cyclohexanes; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Hydroxamic Acids; Interferon-alpha; Interleukin-12; Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Phenylalanine; Platelet Factor 4; Polysaccharides, Bacterial; Sesquiterpenes; Thalidomide; Thiophenes; Triazines; Triazoles; Tumor Cells, Cultured

In anti-cancer therapy, current investigations explore the possibility of two different strategies to target tumor vasculature; one aims at interfering with angiogenesis, the process involving the outgrowth of new blood vessels from pre-existing vessels, while the other directs at affecting the already established tumor vasculature. However, the majority of in vitro model systems currently available examine the process of angiogenesis, while the current focus in anti-vascular therapies moves towards exploring the benefit of targeting established vasculature as well. This urges the need for in vitro systems that are able to differentiate between the effects of compounds on angiogenesis as well as on established vasculature. To achieve this, we developed an in vitro model in which effects of compounds on different vascular targets can be studied specifically. Using this model, we examined the actions of the fumagillin derivate TNP-470, the MMP-inhibitor marimastat and the recently developed tubulin-binding agent Ang-510. We show that TNP-470 and marimastat solely inhibited angiogenesis, whereas Ang-510 potently inhibited angiogenesis and caused massive disruption of newly established vasculature. We show that the use of this in vitro model allows for specific and efficient screening of the effects of compounds on different vascular targets, which may facilitate the identification of agents with potential clinical benefit. The indicated differences in the mode of action between marimastat, TNP-470 and Ang-510 to target vasculature are illustrative for this approach.

Topics: Angiogenesis Inhibitors; Animals; Benzene Derivatives; Capillaries; Cyclohexanes; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Hydroxamic Acids; In Vitro Techniques; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; O-(Chloroacetylcarbamoyl)fumagillol; Organophosphorus Compounds; Sesquiterpenes; Tubulin Modulators