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[7][“Inhibitor L”

The genetic heterogeneity of the angiogenic response is another reason for the pressing need to develop blood or urine biomarkers to optimize the dosing of antiangiogenic therapy.Furthermore, when mice are used for preclinical studies of angiogenesis inhibitors, it is crucial to know the genetic background of the mice in regards to their angiogenic responsiveness.However, as in some cases including cancer, antiangiogenic therapies can also be used in combination with existing drugs.Importantly, antiangiogenic therapy primarily targets the activated microvascular endothelial cells in a tumour bed rather than the tumour itself.Antiangiogenic therapy can also inhibit endothelial cell proliferation and motility indirectly by suppressing a tumours production of angiogenic proteins, as erlotinib does, or by neutralizing one of these proteins, as bevacizumab does.Also, although chemotherapy is usually more effective on alanine rapidly growing tumours than on slowly growing tumours, the opposite is often true of antiangiogenic therapy.More rapidly growing tumours can require higher doses of antiangiogenic therapy.Furthermore, chemotherapy is optimally given at a maximum tolerated dose, with offtherapy intervals of weeks to rescue bone marrow and intestine.Antiangiogenic therapy might optimally require that endothelial cells be exposed to steady blood levels of the inhibitor.Therefore, daily dosing is optimal for those angiogenesis inhibitors with a short halflife.However, certain antibodies such as bevacizumab can be administered every weeks because of longlasting antibody levels in plasma, and perhaps because of neutralization of VEGF in platelets by bevacizumab that enters the platelets and binds with VEGF.Zoledronate is an aminobisphosphonate that has been shown to inhibit angiogenesis by targeting matrix metalloproteinase, by reducing circulating levels of proangiogenic proteins in the circulation or by suppressing multiple circulating proangiogenic factors in patients with cancer.It accumulates in bone and can therefore be administered every month.However, after prolonged use, zoledronate may need to be administered less frequently to avoid osteonecrosis of the jaw.Another important difference concerns the side effects of antiangiogenic therapy compared with chemotherapy.Bonemarrow suppression, hair loss, severe vomiting and diarrhoea, and weakness are less common with antiangiogenic therapy, and endostatin has shown minimal or no side effects in animals and in humans.It has to be noted though, that certain angiogenesis inhibitors increase the incidence of thrombotic complications, such as thalidomide and bevacizumab.The risk of thrombosis is increased when these angiogenesis inhibitors are administered together with conventional chemotherapy.Iressa blocks tumour expression of an angiogenic factor.Side effects need to be carefully considered, especially when antiangiogenic and cytotoxic medications are combined.So far, there are almost no data that allow a direct Fluorouracil comparison of clotting risk for antiangiogenic therapy alone, compared with cytotoxic therapy or combination therapy.However, there can also be unexpected benefits from combining angiogenesis inhibitors, or drugs that have varying degrees of antiangiogenic activity, with conventional chemotherapy.In other words, antiangiogenic therapy might normalize tumour vessels.Biphasic dose efficacy of antiangiogenic therapy.Dose efficacy is generally a linear function for chemotherapy.It is now clear that blood levels of certain angiogenesis inhibitors that are too high or too low will be ineffective, and that the biphasic doseefficacy curve offers the best explanation for why endostatin gene therapy of murine leukaemia failed.

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