Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.
Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.
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DOI：
10.1371/journal.pone.0003593
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Gottesfeld JM
中科院分区：
文献类型：
--
作者：
Chou CJ;O'Hare T;Lefebvre S;Alvarez D;Tyner JW;Eide CA;Druker BJ;Gottesfeld JM
慢性粒细胞白血病（CML）的特征在于存在组成型活性Abl激酶，其是由称为费城染色体的遗传易位引起的嵌合BCR-ABL基因的产物。伊马替尼是一种选择性Bcr-Abl酪氨酸激酶抑制剂，可显著改善CML患者的临床结局。然而，通过出现伊马替尼耐药细胞，患者亚群失去了对治疗的反应，并且伊马替尼治疗对晚期CML患者的持久性较低。虽然替代Bcr-Abl酪氨酸激酶抑制剂已被开发，以克服耐药性，鸡尾酒疗法的不同激酶抑制剂和额外的化疗药物可能需要在某些情况下，CML的完全缓解。苯丁酸氮芥已用于治疗B细胞慢性淋巴细胞白血病、非霍奇金病和霍奇金病。在这里，我们报告的DNA序列特异性吡咯-咪唑聚酰胺-苯丁酸氮芥共轭物，1 R-Chl，导致生长停滞的细胞窝藏未突变的BCR-ABL和三个伊马替尼耐药菌株。1 R-Chl还在鼠模型中显示出对活化的淋巴细胞的选择性毒性和高剂量耐受性。
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.
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影响因子：
5.7
作者：
Chou, C. James;Farkas, Michelle E.;Gottesfeld, Joel M.
通讯作者：
Gottesfeld, Joel M.
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
4.3
作者：
Alvarez, David;Chou, C. James;Gottesfeld, Joel M.
通讯作者：
Gottesfeld, Joel M.
影响因子：
64.8
作者：
ROWLEY, JD
通讯作者：
ROWLEY, JD
影响因子：
14.9
作者：
Tsai SM;Farkas ME;Chou CJ;Gottesfeld JM;Dervan PB
通讯作者：
Dervan PB