Chou C James, O'Hare Thomas, Lefebvre Sophie, Alvarez David, Tyner Jeffrey W, Eide Christopher A, Druker Brian J, Gottesfeld Joel M
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
PLoS One. 2008;3(10):e3593. doi: 10.1371/journal.pone.0003593. Epub 2008 Oct 31.
Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.
慢性粒细胞白血病（CML）的特征是存在一种组成型激活的Abl激酶，它是由称为费城染色体的基因易位导致的嵌合BCR-ABL基因的产物。伊马替尼是一种Bcr-Abl酪氨酸激酶的选择性抑制剂，显著改善了CML患者的临床结局。然而，部分患者会因出现伊马替尼耐药细胞而失去对治疗的反应，且伊马替尼治疗对晚期CML患者的持久性较差。尽管已开发出替代的Bcr-Abl酪氨酸激酶抑制剂来克服耐药性，但在某些情况下，可能需要不同激酶抑制剂和其他化疗药物的联合疗法才能使CML完全缓解。苯丁酸氮芥已用于治疗B细胞慢性淋巴细胞白血病、非霍奇金淋巴瘤和霍奇金病。在此我们报告，一种DNA序列特异性的吡咯-咪唑聚酰胺-苯丁酸氮芥偶联物1R-Chl可导致携带未突变BCR-ABL和三种伊马替尼耐药菌株的细胞生长停滞。1R-Chl在小鼠模型中还表现出对活化淋巴细胞的选择性毒性和高剂量耐受性。
