Angiogenesis inhibitors have therefore shown promise in animal studies, and clinical trials are underway.Animal studies reveal that many angiogenesis inhibitors are most effective when administered by a dose and schedule that maintains a constant concentration of the inhibitor in the circulation, rather than a oncedaily bolus therapy.Cytotoxic drugs, by contrast, are usually administered at maximum tolerated doses followed by offtherapy intervals.The anticancer drug TNP is a synthetic analogue of fumagillin.It selectively inhibits methionine aminopeptidase, blocks the activ ity of the cyclindependent kinase CDK, and inhibits phosphorylation and activationof the retinob lastoma protein.In the best results of early clinical tr ialswith this drug, of patients exper ienced a Tetracycline hydrochloride regression of tumour volume.Furthermore, five patien ts exper ienced a comp le te or dramatic and durable tumour regression, despite hav ing failed all conventional therapy.Nevertheless, tumour regression by antiangiogenic therapy is slow, and can take more than year. This is in contrast to the re latively rapid tumour regression that can be obtained by cytotoxic chemotherapy.The clinical end points that are used to determine efficacy of cy totoxic agents, therefore, do not always app ly to antiang iogen ic therapy.The term s tab le disease illustrates this dilemma.If a cy totoxic drug br ingsabout stabil izat ion, but not tumour reg ression, the drug might be considered a failure by some onco log is ts because the tumourwill even tually become resistant to the drug, and tumour growth will resume.But acquired resistance might not be as serious a threat with some angiogenesis inhibitors as it iswith chemotherapeutics, so tumourgrow th can be ar res ted for longtime per iods. But how do antiangiogenic drugs exert their antitumour effects, and what are the most reliable end points for determining therapeutic efficacy?Untreated tumours usually become hypoxic as their size increases.Radiological images or angiograms of large tumours often reveal a dark ischaemic central area that is surrounded by a rim of vascularized tumour tissue.A clear line of demarcation exists between live tumour cells, which arewithin the oxygen diffusion limit of an open Zolmitriptan microvessel, and dead tumour cells that lie a few microns beyond this limit. This is commonly interpreted to mean that the tumour has outgrown its blood supply.It is more likely, however, that elevated tissue pressure that is secondary to vascular leakage has compressed the tumour vasculature.These compressed areas become ischaemic, and foci of necrosis appear, surrounded by regions of hypoxia.Tumours produce proangiogenic proteins to overcome hypoxia.Hypoxic conditions allow activation of the transcription factor HIF, which induces expression of VEGF and other genes that are involved in angiogenesis induction. HIF activity is an unfavourable prognostic indicator in earlystage invasive cervical cancer and in the response of oropharyngeal cancers to radiotherapy. In normal tissues, VEGF is upregulated and its mRNA stabilized only under conditions of hypoxia.In tumour cells, by contrast, VEGF is constitutively overexpressed, independently of the ambient oxygen tension, but can be further increased by hypoxia. Loss of vasculature causes tumour cells to undergo growth arrest or become apoptotic. This tumourcell death was initially thought to be caused by reduced deliveryof oxygen to the tumour.