Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies

Abstract

Although the alkylating agents were amongst the first non-hormonal compounds to be shown to be active against malignant cells they still rank as some of the most valuable cytotoxic drugs available for the treatment of patients with leukaemia and lymphoma. Melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide and the nitrosoureas are all members of this class of drug, which are believed to exert their cytotoxic effects through the covalent linkage of alkyl groups to DNA. In the first report describing the use of alkylating agents in clinical practice the problem of drug resistance was recognised. In spite of this there is still comparatively little known about the mechanisms underlying the development of resistance as it occurs in patients. Studies using animal models and cell lines have suggested that both cellular and extracellular factors may be involved, but the precise relevance of these to the clinical setting is unclear. A greater understanding of the mode of action and mechanisms of resistance to alkylating agents should enable the development of modulators capable of the restoration of sensitivity to resistant cells, and the more effective use of these well established drugs.