DRUG STUDY AND INFORMATION FORM Generic Name: Bendamustine (Nitrogen Mustard) Trade Name: Ribomustin, Treanda Drug

Class: Alkylating Agents and Platinum Coordination Complexes Structure/Chemistry: Typical chloroethyl reactive groups attached to a benzimidazole backbone (a purine-like structure)

Pharmacodynamics

Mechanism of Action: The reactive intermediates from adducts through crosslinks with intra- and interstand DNA at guanine N7 positions (preferential target). The alkylated guanine becomes more acidic, favoring an enol tautomer, which can mispair with thymine. Alkylation at guanine N7 can also lead to imidazole ring opening and excision of the damaged guanine residue.

Pharmacologic Effects: Produces slowly repaired DNA cross-links while lacking crossresistance with other classical alkylators. Induces cell cycle arrest through extensive DNA damage. Apoptosis of the cell is dependent on an intact p53 response and the abilities of the DNA repair systems. Causes cell death in rapidly proliferating tissues.

Drug Resistance or Tolerance: Develops rapidly when used as a single agent. Resistance due to decreased permeation of actively transported drugs, increased intracellular concentrations of nucleophilic substances (thiols such as glutathione that can conjugate with and detoxify intermediates), increased activity of DNA repair pathways, increased degradation of activated forms, detoxification by glutathione transferases, loss of ability to recognize adducts as the result of defective MMR, and impaired apoptotic pathways

Pharmacokinetics

Absorption: Given as a 30-min IV infusion of 100 mg/m2/day on days 1 and 2 of a 28 day cycle. Distribution:

Elimination: t1/2 of 30 mins. Maximal plasma concentration reached at 1 hour. Degraded by sulfhydryl interaction and adduct formation with macromolecules

Metabolism: Extensively metabolized in the liver by cytochrome p450s. N-demethylation and oxidation produces metabolites that have antitumor activity, but less than that of the parent drug. Adverse Side Effects/Toxicity: Rapidly reversible myelosuppression and mucositis, intestinal denudation, alopecia, nausea, and vomitting. Drug Interactions:

Therapeutic uses: CLL (chronic lymphocytic leukemia) and non-Hodgkins lymphoma

Miscellaneous: