The effects of antiang iogenics on other therapies.This might explain why some tumours increase their size before decreasing it during antiangiogenic therapy.Although these experiments were Ritodrine hydrochloride shortterm, the presumed mechanism was that antiangiogenic agents decreased leakage of plasma proteins from tumour vessels, resulting in decreased intratumoral pressure.Weischelbaum and colleagues subsequently reported that the efficacy of ionizing radiation was improved by coadministration of the angiogenesis inhibitor angiostatin, when administered at a dose that would be ineffective for angiostatin alone.The optimal design of a clinical trial for an angiogenesis inhibitor would therefore be to provide for longterm therapy with assessment of tumour blood flow at consistent time intervals.If a patients tumour progresses during therapy, a provision in the trial design to increase the dose of inhibitor might halt tumour progression or bring about the Ropivacaine hydrochloride original stable state.In one experimental tumour system, endothelialapoptos is preceded tumourcell apoptosis by days. At least of these proteins have been repor ted to be produced by endothelial cells, PDGF, IL and hepar inbinding epithelial grow th factor, among others.Production of paracrine factors is decreased, in part, because angiogenesis inhibitors can inhibit endothelialcell proliferation.It is unclear whether angiogenesis inhibitors also directly decrease endothelialcell production of paracrine factors.Because antiangiogenic therapy does not shut off DNA synthesis in tumour cells at least at the beginning of therapy these cells should remain susceptible to chemotherapy, unless they have acquired drugresistance mechanisms.Although addition of an ang iogenesis inhibitor to lowdose, metronomic chemotherapy had a synergistic effect on the inhibition of tumour grow th in mice, it remains to be determined whether conventional chemotherapy can be improved by combining it with an angiogenesis inhibitor.This has been proposed as a mechanism by which tumour cells could become less responsive over time, or even resistant, to antiangiogenic therapy. Tumour cells also become resistant to chemotherapyinduced apoptosis. For example, overexpression of the antiapoptotic protein BCL al lows prostate carcinoma to become refractoryto cy totoxic chemotherapy.Antiang iogenic drugs, however, can also overcome this obstacle.Recent experiments provide additional evidence that angiogenesis inhibitors reduce plasma leakage from tumour vessels. Several clinical studies indicate that despite an increase in tumour blood flow during the early phase of antiangiogenic therapy, chronic antiangiogenic therapy causes total tumour blood flow to reach a steady state or to gradually decrease.When endostatin was continued for weeks or months in cancer patients, positronemission tomography scans revealed a gradual, dosedependent reduction in total tumour blood flow.This could be caused by a dropout of individual microvessels, followed by a loss of the surrounding tumour cells.In addition, there are several ongoing trials that are using noninvasive imaging techniques to assess changes in tumour blood flow following treatment with angiogenesis inhibitors.This is different from hypoxia, which is defined as a low level of oxygen in tissues.There are several other therapeutic manoeuvres that might bypass tumour resistance to apoptosis.Inhibitors of HIF suppress tumour growth and might also act synergistically with angiogenesis inhibitors.The increased neovascularization that occurs following the loss of p function, however, can be overcome by increasing the dose of antiangiogenic therapy.