title: Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo.
abstract: OBJECTIVE
  Bendamustine with or without rituximab provides an effective and more tolerable alternative to the polytherapy cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) in the treatment of haematological tumours and is currently approved for the treatment of many haematological malignancies. Navitoclax (ABT-263) is a potent inhibitor of Bcl-2, Bcl-x(L) and Bcl-w, which has demonstrated efficacy in haematological tumours alone and in combination with other agents. This paper describes the in vivo efficacy of combining either bendamustine or bendamustine plus rituximab (BR) with navitoclax in xenograft models of non-Hodgkin's lymphoma
  
  
  METHODS
  Activity was tested in xenograft models of diffuse large B-cell lymphoma (DoHH-2, SuDHL-4), mantle cell lymphoma (Granta 519) and Burkitt's lymphoma (RAMOS). Activity was also monitored in a systemic model of Granta 519.
  
  
  RESULTS
  Navitoclax potentiated bendamustine activity in all cell lines tested. Bendamustine activated p53 in Granta 519 tumours, concurrent with activation of caspase 3. Navitoclax also improved responses to bendamustine-rituximab (BR) in a subset of tumours.
  
  
  CONCLUSIONS
  Navitoclax in combination with bendamustine and BR is a viable combination strategy for use in the clinic and demonstrated superior efficacy compared with previously reported data for navitoclax plus CHOP and rituximab-CHOP.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Labs, Abbott Park, IL, USA. scott.ackler@abbott.com
authors.forename: S
authors.initials: S
authors.lastname: Ackler
authors.forename: M J
authors.initials: MJ
authors.lastname: Mitten
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Clarin
authors.forename: K
authors.initials: K
authors.lastname: Foster
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.forename: D C
authors.initials: DC
authors.lastname: Phillips
authors.forename: S
authors.initials: S
authors.lastname: Schlessinger
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: Leverson
authors.forename: E R
authors.initials: ER
authors.lastname: Boghaert
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000069461:Bendamustine Hydrochloride; D045744:Cell Line, Tumor; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D000069283:Rituximab; D013449:Sulfonamides / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; C528561:navitoclax