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      Display technologies: Application for the discovery of drug and gene delivery agents

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          Abstract

          Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed.

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          Cancer genes and the pathways they control.

          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines.

            We describe here the development and implementation of a pilot-scale, in vitro, anticancer drug screen utilizing a panel of 60 human tumor cell lines organized into subpanels representing leukemia, melanoma, and cancers of the lung, colon, kidney, ovary, and central nervous system. The ultimate goal of this disease-oriented screen is to facilitate the discovery of new compounds with potential cell line-specific and/or subpanel-specific antitumor activity. In the current screening protocol, each cell line is inoculated onto microtiter plates, then preincubated for 24-28 hours. Subsequently, test agents are added in five 10-fold dilutions and the culture is incubated for an additional 48 hours. For each test agent, a dose-response profile is generated. End-point determinations of the cell viability or cell growth are performed by in situ fixation of cells, followed by staining with a protein-binding dye, sulforhodamine B (SRB). The SRB binds to the basic amino acids of cellular macromolecules; the solubilized stain is measured spectrophotometrically to determine relative cell growth or viability in treated and untreated cells. Following the pilot screening studies, a screening rate of 400 compounds per week has been consistently achieved.
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              Systematic variation in gene expression patterns in human cancer cell lines.

              We used cDNA microarrays to explore the variation in expression of approximately 8,000 unique genes among the 60 cell lines used in the National Cancer Institute's screen for anti-cancer drugs. Classification of the cell lines based solely on the observed patterns of gene expression revealed a correspondence to the ostensible origins of the tumours from which the cell lines were derived. The consistent relationship between the gene expression patterns and the tissue of origin allowed us to recognize outliers whose previous classification appeared incorrect. Specific features of the gene expression patterns appeared to be related to physiological properties of the cell lines, such as their doubling time in culture, drug metabolism or the interferon response. Comparison of gene expression patterns in the cell lines to those observed in normal breast tissue or in breast tumour specimens revealed features of the expression patterns in the tumours that had recognizable counterparts in specific cell lines, reflecting the tumour, stromal and inflammatory components of the tumour tissue. These results provided a novel molecular characterization of this important group of human cell lines and their relationships to tumours in vivo.
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                Author and article information

                Contributors
                Journal
                Adv Drug Deliv Rev
                Adv. Drug Deliv. Rev
                Advanced Drug Delivery Reviews
                Elsevier Science Publishers, B.V
                0169-409X
                1872-8294
                6 October 2006
                30 December 2006
                6 October 2006
                : 58
                : 15
                : 1622-1654
                Affiliations
                [a ]Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
                [b ]Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
                [c ]Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
                Author notes
                [* ]Corresponding authors. Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA. rpasqual@ 123456mdanderson.org warap@ 123456mdanderson.org
                [1]

                Authors contributed equally to this work.

                Article
                S0169-409X(06)00182-7
                10.1016/j.addr.2006.09.018
                1847402
                17123658
                c6a3a770-3f31-45e1-a857-20da13a83c85
                Copyright © 2006 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 26 September 2006
                : 29 September 2006
                Categories
                Article

                combinatorial peptide libraries,vascular cell surface proteomics,targetomics,targeted therapies,display scaffold,phage display,viral display,bacterial display,yeast display,cell display,ribosome display,mrna display,covalent dna display

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