Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

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Clinical Cancer Research 14, 309-317, January 1, 2008. doi:

10.1158/1078-0432.CCR-07-1061

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique

Mechanistic Features Compared with Other Alkylating Agents

Lorenzo M. Leoni1,2, 1,3, Jack Reifert1,6, H. Bendall1,4,

W. Zeller3, Jacques Corbeil7,9, Elliott1,5 and C.

Niemeyer1,8

Authors' Affiliations: 1 Salmedix, acquired by Cephalon, Inc., Frazer,

Pennsylvania; 2 Telormedix, Lugano, Switzerland; 3 Department of Biology, San

Diego State University; 4 Neurocrine, Inc.; and 5 Galenic Strategies, San Diego,

California; 6 University of California Santa Barbara, Santa Barbara, California;

7 Center for AIDS Research, Center for Molecular Medicine and Cancer Center,

University of California San Diego and 8 Burnham Institute for Medical Research,

La Jolla, California; and 9 Quebec City Genome Centre, Laval University, Quebec,

Canada

Requests for reprints: Niemeyer, Burnham Institute for Medical

Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone:

858-646-3100; Fax: 858-795-5221; E-mail: niemeyer@... .

Purpose: 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.

Experimental Design: 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.

Conclusion: These results suggest that bendamustine possesses mechanistic

features that differentiate it from other alkylating agents and may contribute

to its distinct clinical efficacy profile.