title: In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia.
abstract: OBJECTIVE
  The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan.
  
  
  METHODS
  Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation.
  
  
  RESULTS
  Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels.
  
  
  CONCLUSIONS
  Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML.
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radujkovic
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
authors.forename: Peter
authors.initials: P
authors.lastname: Dreger
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: W
authors.initials: W
authors.lastname: Jens Zeller
authors.forename: Stefan
authors.initials: S
authors.lastname: Fruehauf
authors.forename: Julian
authors.initials: J
authors.lastname: Topaly
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives; D049109:Cell Proliferation / Q000187:drug effects*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D019172:Transplantation Conditioning; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; C048341:mafosfamide; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; C018404:treosulfan; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D002066:Busulfan