Expert review of anticancer therapy
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Expert Rev Anticancer Ther · Feb 2005
ReviewMolecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 4: p53 signaling pathway.
Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Loss of the tumor suppressor gene p53 and its encoded protein are the most common genetic events in human cancer and are a frequent occurrence in brain tumors. p53 functions as a transcription factor and is responsible for the transactivation and repression of key genes involved in cell growth, apoptosis and the cell cycle. ⋯ Molecular therapeutic strategies to normalize p53 signaling in cells with mutant p53 include pharmacologic rescue of mutant protein, gene therapy approaches, small-molecule agonists of downstream inhibitory genes, antisense approaches and oncolytic viruses. Other strategies include activation of normal p53 activity, inhibition of mdm2-mediated degradation of p53 and blockade of p53 nuclear export. Further development of targeted therapies designed to restore or enhance p53 function, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.
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Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. Over the past several years, a number of clinical trials have demonstrated the clinical activity of alemtuzumab in treating patients with chronic lymphocytic leukemia, T-cell malignancies such as T-prolymphocytic leukemia and cutaneous T-cell lymphoma, as well as in the prevention and therapy of graft-versus-host disease in the setting of allogeneic stem cell transplantation. ⋯ The most significant side effect of alemtuzumab is predisposition to infections related to the associated profound lymphopenia. Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future.