Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents.
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.
Leoni
Lorenzo M
LM
Salmedix, acquired by Cephalon, Inc., Frazer, Pennsylvania, USA.
Bailey
Brandi
B
Reifert
Jack
J
Bendall
Heather H
HH
Zeller
Robert W
RW
Corbeil
Jacques
J
Elliott
Gary
G
Niemeyer
Christina C
CC
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*
D018906:Antineoplastic Agents, Alkylating; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride