Cyclophosphamide (CP) and its analogs are widely used in bone marrow transplantation for myeloid leukemias (MLs). A major perceived clinical problem is the development of leukemic cell resistance to CP, with subsequent clinical resistance and progressive disease. The applicant hypothesizes that A) a significant component of clinical resistance to CP does in fact derive from tumor cell resistance, B) while elevated aldehyde dehydrogenase (ALDH) is a major contributor to tumor-cell resistance, additional genetic mechanisms are also important factors in the resistance of ML to CP analogs, and C) an increased understanding of CP resistance will yield strategies for its prevention, or once it has developed, for its circumvention. To this end, the applicant proposes to study human leukemic cell lines with experimentally-induced resistance to the in vitro active CP analogs 4-hydroperoxycyclophosphamide and phosphorodiamidic mustard. Specifically the applicant will: 1) define the biochemical mechanisms of leukemic cell resistance to in vitro active CP analogs, 2) define the genetic characteristics of each cell line using comparative genomic hybridization and differential display of mRNA to identify consistent genetic resistance markers, and 3) apply the information gained from the above studies to generate a panel of molecular probes that can ultimately be used to interface with techniques such as fluorescent in situ hybridization and flow cytometry to enable a critical evaluation of the hypothesis that a significant component of clinical resistance to CP analogs does indeed derive from tumor-cell resistance.
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