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Inhibitor Irreversible

Indirect angAnidulafungin iogenesis inhibitors generally prevent the expression of or block the activity of a tumour protein that activates angiogenesis, or block the expression of its receptor on endothelial cells. Many of these tumourcell proteins are the products of oncogenes that dr ive the ang iogenic sw itch. The activ ities of oncogene and tumoursuppressor gene products were initially studied in invitro assays that monitored cancercell proliferation, apoptosis resistance, immortalization and anchorage independence. Because the increased cancercell proliferation and decreased apoptosis that was associated with oncogene activation in vitro correlated so well with tumour grow th invivo, there was no reason to suspect that these new anticancer drugs could also block the Losartan potassium angiogenic output of a tumour.Direct angiogenesis inhibitors, such as endostatin, target the microvascular endothelial cells that are recruited to the tumour bed and prevent them from responding to various endothelial mitogens and motogens.Indirect angiogenesis inhibitors, such as ZD, target proteins such as epidermal growthfactor tyrosine kinase and its products bFGF, VEGF and TGF, or their receptors, on endothelium that are expressed by tumour cells.In another study, human osteosarcoma cells that were imp lanted inmice formed on lymicroscop ic avascular, dormant tumours in which cancercell proliferation was balanced by apoptosis.So, targeting oncogene products not only affects cancercell proliferation and cell death, but also disrupts the product ion of ang iogen ic factors. React ivat ion of tumour suppressors such as p can a lso inh ib it angiogenesis by different mechanisms, which are discussed below. These studies predict that certain anticancer drugs that were developed for their capacity toblock an oncogene product would have indirect antiangiogenic activity. Indeed, RAS farnesy ltransferase inh ib itorsblock oncogenesignalling pathways that upregulate tumourcell product ion of VEGF and downregu late product ion of the angiogenesis inhibitor thrombospondin. It is important for clinical researchers to recognize that anticancer drugs that target an oncogene product can inhibit angiogenesis, as this can affect drug dose and schedule.A drug that inhibits angiogenesis indirectly might be discontinued prematurely because of resistance, which is determined by increased tumour ang iogenesis.Instead, a second inhibitor could be added to the therapeutic reg imen.For example, trastuzumab an antibody that blocks ERBB receptor tyrosine kinase signalling, suppresses cancercell production of angiogenic factors such as TGF, ang iopoietin and plasminogenactivator inhibitor, and possibly also VEGF.It also upregulates the expression of an ang iogenesis inhibitor, thrombospondin.If the tumour, however, begins to express a different angiogenic protein, such as bFGF or IL, the tumour under treatment might seem to have become resistant to trastuzumab, and the therapy will be discontinued.But this practice might not be prudent for a drugwith significant antiang iogenic activ ity it might be more effective to add a second antiang iogenic drug to the regimen.It is of interest that certain tumours, such as giantcell tumours of the bone and angioblastomas, only or mainly produce a single angiogenic factor bFGF.Cells also produce their own endogenous inhibitors of angiogenesis, such as thrombospondins, which can be developed as therapeutics.Transgenic expression of matricellular glycoproteins thrombospondin and reduces the size and density of tumour vessels and reduces tumour growth in nude mice of human squamouscell carcinoma.

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