Steam Library

There are currently more than repor ts from different laboratories on the ability of this drug to inhibit different types of primary tumours and different types of metastatic tumours in animal models.One explanation for this phenomenon is that when an angiogenesis inhibitor is not sufficiently potent to completely suppress metastases after it partially inhibits the primary tumour, the reduced production of endogenous inhibitor from the primary tumour allows growth of the metastases.These drugs were shown to have very low toxicity, and acquired drug resistance was rarely seen in animals that weretrea ted for pro longed per iodsoftimewi th ang ios tatin or endos tatin. Th is does notmean thatrelapses, due to a loss of response to direct angiogenes is inh ibitors, will never occur. As recently described, there are epigenetic mechanisms of resistance thatcan comprom ise theefficacyofdirectang iogenes is inh ib itors overtime, espec ially when these drugs are used as monotherapies.Fortunately, there is a large and diverse number of angiogenic targets. Drug comb inat iontherapy reg imens inmice have resulted in pro longed anti tumour responses, while avoiding or Glimepiride delaying resistance. Here, we have selected a few tr ials, that have prov ided impor tant information about the clinical applications of these drugs.A prospective randomized trial of an antibody against VEGF, bevacizumab, in patients with metastatic renalcell cancer the first of its kind for an angiogenesis inhbitor significantly prolonged the time to tumour progression with minimal toxicity, but tumour progression was rare.The primary efficacy end point an increase in the median time of progressionfree survival was not attained, nor was an increase in month survival detected.The failure of this trial might have been due to the fact that only a small number of the patients tumours actually expressed biologically active VEGF, highlighting the need to better characterize tumours before patients are included in trials of molecularly targeted therapeutics.Chemotherapeutic agents have also been shown to have antiangiogenic properties in animal models, in addition to their ability to induce direct cancercell death.Paclitaxel, which inhibits microtubule polymerization, R E V I E W S inhibits vascular endothelialcell proliferation, motility and invasiveness in a dosedependent manner in vitro and tumour angiogenesis invivo. Secondary effects such as these could contribute to the antitumour efficacy of chemotherapy in vivo and might delay or prevent the Glimepiride acquisition of drug resistance by cancer cells.This could be because chemotherapy is usually administered at the maximum tolerated dose, followed by a treatmentfree interval to allow recovery of bonemarrow and gastrointestinaltract cells.During the treatmentfree interval, microvascular endothelial cells in the tumour bed can resume their proliferation and support tumour regrowth.Antiangiogenic chemotherapy was first shown to be effective in tumourbearing mice.Administration of cyclophosphamide at more frequent intervals and at an overall lower dose with a brief treatmentfree interval induced sustained apoptosis of endothelial cells in the vascular bed of the tumours, and more effectively controlled growth of drugresistant tumours.This protocol also reduced side effects and avoided bonemarrow suppression.These results indicated that antitumour efficacy of cytotoxic drugs might be improved by changing the schedule and dose to provide optimum cytotoxic targeting of the microvascular endothelial cells in the tumour bed.

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