title: Metabolism and mechanisms of action of bendamustine: rationales for combination therapies.
abstract: Bendamustine hydrochloride is the active ingredient of Ribomustin (Ribosepharm GmbH, Munich, Germany). It was first synthesized in 1963 in the German Democratic Republic. Bendamustine is chemically related to the alkylating agent chlorambucil, with the benzene ring in the chlorambucil molecule replaced by a 1-methyl-benzimidazole moiety. The mechanisms of action of bendamustine have been under investigation since the early 1960s, and its first use was as a treatment for multiple myeloma in 1969. Bendamustine has three active moieties: an alkylating group, in common with the nitrogen mustard family; a benzimidazole ring, which may act as a purine analog; and a butyric acid side-chain. Bendamustine undergoes extensive first-pass metabolism. However, unmetabolized bendamustine accounts for about 45% of the total drug recovered in urine. The main transformation product is a cytotoxic hydroxy metabolite (beta-hydroxybendamustine). Bendamustine was originally synthesized with the intention of producing an antineoplastic agent with low toxicity and both alkylating and antimetabolic properties. However, it has been shown that, at least at high concentrations, it acts primarily as an alkylating agent. Based on the multiple actions and cell cycle effects of this agent, mechanism-based combination strategies have been suggested. The rationales behind bendamustine combination regimens and the importance of the sequence of administration of different drugs are explored.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069461:Bendamustine Hydrochloride; D002699:Chlorambucil / Q000737:chemistry; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D016196:S Phase / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007155:Immunologic Factors; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil; D000069461:Bendamustine Hydrochloride