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* From the Department of Radiation Biology (Drs. N. Pedersen, M.W. Pedersen, and H.S. Poulsen, Mr. T.T. Poulsen, and Mss. Mortensen and Sørensen), Institute for Inflammation Research (Drs. Rieneck and Bovin), National University Hospital, Copenhagen, Denmark.
Correspondence to: Hans Skovgaard Poulsen, MD, DrMedSci, Chief Physician, Department of Radiation Biology, Finsen Center, Section 6321, National University Hospital, DK-Copenhagen 2100, Denmark;
With the purpose of identifying novel targets for the diagnosis, staging, and treatment of small cell lung cancer (SCLC), a global gene expression analysis using oligonucleotide microarrays (Affymetrix; Santa Clara, CA) was performed on a large number of human SCLC cell lines and their xenografts. The expression was compared to the expression profiles of 18 normal human tissues.
The analysis confirmed the high expression of a number of genes that previously had been identified as highly being expressed in SCLC, including neuroendocrine markers, oncogenes, and genes involved in cell proliferation and division. However, the analysis also identified a number of molecules that had not previously been associated with SCLC. Several of these are expressed in low or undetectable amounts in the majority of normal tissues and, therefore, are potential targets for new therapeutic approaches. By comparison with the published array profiles of five resected SCLC tumors,1 we found that most of these potential targets also were expressed in tumors and, therefore, were bona fide targets.
Several of the novel identified targets are surface molecules, and therefore are potential targets for diagnostic and therapeutic approaches, such as positron emission tomography imaging, and for radiotherapy. Some of these surface molecules are internalizing receptors, and therefore are potential targets for radiotherapy, toxin therapy, and gene therapy. The expression of several of these surface molecules on a protein level has been verified by Western blotting, and the receptors are currently under investigation for functionality in ligand binding.
Many other genes have been found with high and cancer-specific expression. Some of these may be directly involved in a malignant phenotype, such as oncogenes, and are therefore potential targets in themselves. Others with unknown functions may be able to confer high and cancer-specific gene expression, and are therefore candidates for use in gene therapy for the cancer-specific expression of a therapeutic gene.
Gene expression analysis also was used for a hierarchical cluster analysis, which revealed that the cell lines grouped into four subclusters, two of which contained the classic SCLC cell line types and one of which contained the variant types. The distinction between these types has previously been made in only a few gene products, and the analysis therefore has identified many additional genes with differential expression between the two types of SCLC.
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