CLADRIBINE AS A DNA METHYLATION INHIBITOR IN CHRONIC LYMPHOCYTIC LEUKEMIA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。使用DNA甲基转移酶（DNMT）抑制剂治疗癌症具有合理的分子基础，尽管使用DNMT抑制剂如地西他滨（脱氧胞苷类似物）的临床反应令人失望。骨髓发育不良和急性髓性白血病患者对地西他滨的临床反应是否与DNMT抑制作用有关尚不清楚。此外，我们不知道通过抑制所有三种DNMT同工酶来抑制DNA甲基化是否会导致主要的细胞死亡效应。DNA甲基化沉默的原癌基因也可能被甲基化抑制剂重新激活，尽管这是一种不良影响，但长期治疗可能导致致突变的副作用。我们将验证2-氯-2-脱氧腺苷（cladribine，一种化疗药物）是DNA甲基化抑制剂的假设。

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.