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Inhibitor Binds To A Site On The Enzyme That Is Not The Active Site

Patientswith slowgrow ing cancers who are on antiangiogenic scheduling of chemotherapy involving continuous infusion of fluorouracil, weekly paclitaxel, or daily oral Entecavir hydrate etoposide have shown an improved outcome despite the fact that in some of these patients the tumours had already become resistant to conventional chemotherapy.Antiangiogenic chemotherapy has also been Dimenhydrinate called metronomic therapy, but the two terms do not have precisely the same meaning. Antiangiogenic chemotherapy signifies that the target of the chemotherapy is the microvascular endothelium in the tumour bed.This protein can be detected in the urine and its concentration correlates directly with tumour volume.By, cellular levels of another angiogenic protein vascular endothelial growth factor were reported to predict the outcome of patients with multiple myeloma.The figure shows a comparison of normal versus leukaemic bone marrow, with blood vessels shown in red.In the left panel, normal bone marrow shows normal microvasculature of uniformsized vessels.In the right panel, bone marrow from a child with newly diagnosed acute lymphoblastic leukaemia reveals intense neovascularization, with microvessels of variable diameters.Angiogenesis inhibitors might therefore be useful in treating haematological malignancies.A recent study reported that the retroviral gene transfer of a vector encoding the direct angiogenesis inhibitors angiostatin and endostatin inhibits bonemarrow angiogenesis and tumour growth in a mouse model of leukaemia.This therapy was shown to directly inhibit endothelial proliferation in vitro, but had no effect on leukaemiacell proliferation.Both DC and lowdosevinblastine treatment indiv idually resulted in significant, but transient, xenograft regression, diminished tumour perfusion and direct inhibition of ang iogenesis.The combination therapy, however, resulted in full and sustained regressions of large established tumours, without an ensuing increase in host toxicity or acquired drug resistance.An antiendoglin antibody was shown to act synergistically with cyclophosphamide in a skin tumoursevere combined immunodeficiency mouse model.Endoglin is a proliferationassociated cellmembrane protein that is expressed on the tumourassociated angiogenic vascular endothelium.It is required for angiogenesis and is a component of the TGF receptor complex.Thalidomide inhibited new bloodvessel formation in rabbits and mice independently of its ability to suppress infiltrating host inflammatory cells.In, thalidomide therapy was shown to be active, in humans, against advanced multiple mye loma. Some of patients who were treatedwith thalidomide had a positive response, as assessed by reduction of the serum levels of myeloma protein and ur ine levels of BENCEJONES PROTEIN.These findings have been confirmed by other studies.In fact, it has become one of the most effective drugs for treating patients with multiple myeloma either as firstline therapy or for the treatment of patients who are resistant to conventional chemotherapy.Thalidomide treatment suppresses the production of tumour necrosis factor, which has been reported to be angiogenic.However, other, more potent inhibitors of TNF such as pentoxifylline and dexamethasone, have little or no activity in corneal angiogenesis assays.Furthermore, TNF inhibitors are not effective in animal models of myeloma or in patients.TNF suppression therefore does not seem to be a main part of thalidomides antiangiogenic activity.Thalidomide does have a direct antiproliferative effect on multiple myeloma cells invitro, although very high concentrations of thalidomide are required.Nevertheless, this drug might be able to target both cancer cells and vascular endothelial cells.

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