title: Dual inhibition of the homologous recombinational repair and the nonhomologous end-joining repair pathways in chronic lymphocytic leukemia therapy.
abstract: Resistance to chlorambucil in chronic lymphocytic leukemia (CLL) has been associated with increased DNA repair. Specifically, inhibition of either c-abl, which modulates Rad51 directed homologous recombination or DNA-PK dependent nonhomologous end joining has been shown to sensitize primary CLL lymphocytes to chlorambucil. Here we report that inhibition of c-abl can result in a compensatory increase in DNA-PK and thus inhibition of both c-abl and DNA-PK optimally sensitizes CLL lymphocytes to chlorambucil. In this paper we report a drug-induced compensatory change between two DNA repair pathways with potential therapeutic implications in CLL therapy.
authors.affiliation: Department of Oncology, Segal Cancer Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
authors.forename: Lilian
authors.initials: L
authors.lastname: Amrein
authors.forename: David
authors.initials: D
authors.lastname: Davidson
authors.forename: May
authors.initials: M
authors.lastname: Shawi
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Petruccelli
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.forename: Raquel
authors.initials: R
authors.lastname: Aloyz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Panasci
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D001549:Benzamides; D015153:Blotting, Western; D002699:Chlorambucil / Q000494:pharmacology*; D020552:Comet Assay; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000628:therapy; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011995:Recombination, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D002699:Chlorambucil; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D051747:DNA-Activated Protein Kinase; C498826:nilotinib