The aim of this project is to integrate three types of information on the molecular pharmacology of cancer: (1) patterns of cancer cell inhibitory activity for compounds tested in the NCI's drug discovery program; (2) molecular structural features of the tested compounds; (3) possible molecular targets and modulators of activity in the cells used for testing. The results have implications for drug discovery and design, for possible individualization of therapy, and for clinical studies of molecular markers on cancer cells. Analytical results to date have included the following: (i) Neural networks able to predict mechanism of drug action on the basis of patterns of activity in DTP's 60-cell line cancer drug screen; (ii) A program package (DISCOVERY) that integrates information on the chemical structure, activity, and possible molecular targets of compounds tested by NCI. As the name suggests, DISCOVERY was designed to search for novel mechanisms of action among the 60,000 compounds tested to date; (iii) Neural nets and statistical methods to predict (with only moderate sensitivity and specificity, it should be stressed) the clinical activity of phase II-evaluable drugs on the basis of patterns of activity in the screen; (iv) Use of DISCOVERY to identify what we term """"""""p53-inverse"""""""" agents, i.e., compounds that appear more active in p53-mutant than in p53-wild type cell lines; (v) QSAR studies and pharmacophore searches in the NCI's DIS database to identify new inhibitors of HIV-1 integrase and human topoisomerase I. Experimental results to date have included (i) Development of a large protein expression database for the 60 cell lines in the NCI drug discovery program (by 2D-gel electrophoresis, in collaboration with Dr. Leigh Anderson, Large Scale Biology Corp.) (ii) Addition to that central database of experimental data on other cell types, including endothelial cells, multi-drug resistant cancer cells, p53-isogenic cell sets, and cell types used for HIV drug discovery; (iii) Development of methods based on matrix-assisted laser desorption ionization mass spectrometry (MALDI) and ion trap electrospray mass spectrometry to identify and characterize proteins in the gels in sub-picomole amounts. This project as a whole represents a collaboration with the NCI Developmental Therapeutics Program, as well as a number of other laboratories.
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