title: Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents.
abstract: OBJECTIVE
  Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds.
  
  
  METHODS
  Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard.
  
  
  RESULTS
  Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.
  
  
  CONCLUSIONS
  These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
authors.affiliation: Salmedix, acquired by Cephalon, Inc., Frazer, Pennsylvania, USA.
authors.forename: Lorenzo M
authors.initials: LM
authors.lastname: Leoni
authors.forename: Brandi
authors.initials: B
authors.lastname: Bailey
authors.forename: Jack
authors.initials: J
authors.lastname: Reifert
authors.forename: Heather H
authors.initials: HH
authors.lastname: Bendall
authors.forename: Robert W
authors.initials: RW
authors.lastname: Zeller
authors.forename: Jacques
authors.initials: J
authors.lastname: Corbeil
authors.forename: Gary
authors.initials: G
authors.lastname: Elliott
authors.forename: Christina C
authors.initials: CC
authors.lastname: Niemeyer
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride