The Tumor Resistance Of New Targets And Lead Compounds Based On Receptor Structure Discovery And Research

In the post-genomic era, researchers are faced with the enormous challenge of translating genomic information into new innovative medicines to improve the human condition. Thousands or more potential new drug targets have emerged as a result of sequencing the human genome, therefore, genomic data can then be used to focus structure-based inhibitor design towards areas of the novel target molecules. If we are to effectively use the fruits of genomic research, we must re-engineer drug discovery and development. There are two key processes in drug discovery today, the identification and validation of new drug targets and the identification and optimization of leads from them.1. Validation of Sorcin, an Important Gene Associated with Multidrug -Resistance in Human Leukemia Cells.Multidrug resistance (MDR) in cancer, especially in leukemia, represents a major obstacle to successful chemotherapies. The mechanisms of MDR are polygenetic and yet to be completely defined. By gene profiling analysis we previously identified 12 genes that showed significantly altered signal density in a doxorubicin-induced MDR leukemia cell line, K562/A02, compared with its parent cells K562. One of the genes significantly up-regulated in K562/A02 cells is sorcin (soluble resistance-related calcium-binding protein). We have also demonstrated that the level of sorcin expression in leukemia patients correlates not only directly with that of the mdr 1 gene, but also inversely with patients' response to chemotherapies and overall prognosis.In this study we have carried out experiments to dissect out the contribution of sorcin by itself to drug resistant phenotype in K562 cells. The full-length sorcin gene was amplified by RT-PCR from K562/A02 leukemia cells, and cloned into pcDNA3.1 eukaryotic expression vector. After transfection of K562 cells with the pcDNA3.1/sorcin and subsequent G418 selection, individual clones were isolated...