Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate.
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.
Chou
C James
CJ
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
O'Hare
Thomas
T
Lefebvre
Sophie
S
Alvarez
David
D
Tyner
Jeffrey W
JW
Eide
Christopher A
CA
Druker
Brian J
BJ
Gottesfeld
Joel M
JM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D001483:Base Sequence / Q000187:drug effects; D001549:Benzamides; D001773:Blood Cells / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009757:Nylons / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D014161:Transduction, Genetic
D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D009757:Nylons; D010879:Piperazines; D011743:Pyrimidines; D002699:Chlorambucil; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl