growth arrest of bcr-abl positive cells with a sequence-specific polyamide-chlorambucil conjugate增长逮捕bcr - abl阳性细胞与sequence-specific polyamide-chlorambucil共轭.pdfVIP

Growth Arrest of BCR-ABL Positive Cells with a Sequence-Specific Polyamide-Chlorambucil Conjugate 1 2 1 1¤ 2 C. James Chou , Thomas O’Hare , Sophie Lefebvre , David Alvarez , Jeffrey W. Tyner , Christopher A. 2 2 1 Eide , Brian J. Druker , Joel M. Gottesfeld * 1 Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America, 2 Oregon Health Science University Cancer Institute, Division of Hematology and Medical Oncology, Portland, Oregon, United States of America Abstract 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