Despite recent advances in cancer genetics and treatment, anticancer drug resistance remains a formidable problem. The long-term goal of this project has been the development of microdetection assays that will ultimately permit individualization of therapy. Through the years, the applicant has focused on understanding the mechanisms of tumor cell resistance to natural product drugs, and has defined both P-glycoprotein-associated multidrug resistance (Pgp-MDR) and altered topoisomerase II-associated MDR, with the idea that a focus on a few targets might permit exploitation for diagnosis or therapy. It is now clear that resistance, even to a single anticancer drug, is a multifactorial phenomenon with multiple genetic changes. Given this panoply of changes, the task of identifying """"""""the"""""""" gene(s) responsible for the phenotype is very challenging. However, if these changes represent a reproducible pattern of gene expression, then it might not matter knowing which gene(s) cause the phenotype if what is desired is knowing whether an expression pattern accurately represents the phenotype. Recent advances in cDNA array technology now make it possible, after all these years; to develop a true """"""""microdetection"""""""" assay that can theoretically detect drug resistant tumor cells. However, application of this methodology to identify a small proportion of therapy resistant cells in an otherwise sensitive tumor population remains problematic. The applicant will develop the idea in this application that marrying methods of gene array, drug action, and analysis of specific genes will be able to provide a profile of such a subpopulation of drug resistant cells. Accordingly, the hypothesis to be tested is that tumor cells from therapy-resistant patients display coordinate expression of drug-resistant genes that can be detected by their molecular and cellular signatures.
The specific aims are: 1) define the basis for the apparent coordinate regulation of the MDR1, MRP, and other genes in relapsed AML through study of MRP regulation, and 2) use gene array methodology to identify patterns of gene expression associated with therapy resistance in AML.
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