CLADRIBINE AS A DNA METHYLATION INHIBITOR IN CHRONIC LYMPHOCYTIC LEUKEMIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The use of a DNA methyltransferase (DNMT) inhibitors in treating cancer has a rational molecular basis even though clinical responses using DNMT inhibitors like Decitabine (deoxycytidine analogs) have been disappointing. It remains unclear if the clinical responses to Decitabine seen in patients with myelodysplasia and acute myelogenous leukemia were related to the DNMT inhibitory effect. In addition, we do not know if inhibition of DNA methylation by inhibition of all three DNMT isoenzymes leads to a predominant cell death effect. Although an undesirable effect, proto-oncogenes silenced by DNA methylation could also be reactivated by a methylation inhibitor and long term therapy might cause mutagenic side effects. We will test the hypothesis that 2-Chloro-2-deoxyadenosine (cladribine, a chemotherapeuic agent) is a DNA methylation inhibitor.