Bendamustine for Cll and Nhl

comorbidities, many patients eventually relapse or do not qualify for standard therapies 1,2. Additional treatment options that improve tolerability while maximizing efficacy are therefore needed in those settings. Bendamustine hydrochloride is a bifunctional alkylating agent with clinical activity across a number of cancers, including breast cancer, small-cell lung cancer, multiple myeloma, cll, indolent nhl, and mcl 2,3. Ozegowski and colleagues first synthesized this agent in the early 1960s at the Institute for Microbiology and Experimental Therapy in the former German Democratic Republic. With the emerging importance of nitrogen mustards as anticancer agents, bendamustine was developed to improve tolerability without sacrificing clinical activity. Although bendamustine has been used extensively for more than 40 years, it was not systematically studied in lymphoproliferative disorders until the 1990s 4. Bendamustine has three structural elements: a 2-chloroethylamine alkylating group, a benzimidazole ring, and a butyric acid side chain 3,5. The 2-chloroethylamine alkylating group is similar to those in other alkylators such as cyclophosphamide, chlorambucil, and melphalan, and the butyric acid side chain resembles that in chlorambucil. To incorporate the antimetabolite properties of benzimidazole, a central ring system was added that is similar to that in purine analogues. As a whole, the bendamustine molecule is more stable than the molecules of other alkylators, and it causes more extensive and more durable damage to dna. However, the extent to which the benzimidazole ring contributes to the antitumour activity of bendamustine is unclear. Although its exact mechanism of action is unknown, bendamustine appears to be unique among chemotherapy agents 3–5. Unlike other alkylating agents, bendamustine primarily targets base excision repair pathways rather than mismatch repair pathways, and it activates dna-damage stress responses, apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, bendamustine is ABSTRACT