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Since the first clinical experiments with nitrogen mustard at Yale in the early 1940s, alkylating agents have played a primary role in cancer treatment (1). The early mustards have gradually been replaced by platinum-based compounds in most regimens for treating epithelial cancers, but remain primary components in the treatment of childhood solid tumors, lymphomas, and adult sarcomas, and in high-dose chemotherapy. As a class, they have the features of the prototypical cytotoxic drugs, with broad antitumor activity, but they adversely affect many normal tissues as well. They share common characteristics of a significant increase in response as doses are escalated: acute toxic effects on bone marrow, epithelium of the gastrointestinal tract, and hair follicles; significant toxicity to lung, heart, and central nervous systems at bone marrow ablative doses; and late induction of myelodysplasia and acute leukemia.


Three general classes of DNA adduct-forming agents have found clinical application. The first are the chloroethyl nitrogen mustards, exemplified by cyclophosphamide, ifosfamide, melphalan, and chlorambucil (Figure 5-1). These drugs become active through formation of a highly reactive imonium intermediate, which transfers its ethyl group to nucleophilic (electronegative) sites on DNA (amino, hydroxyl, or phosphate sites) and to sulfhydrils on amino acids and glutathione (Figure 5-2). These drugs contain two chloroethyl groups and can cross-link DNA, creating a lesion that is difficult to repair. The classical nitrogen mustard was a highly unstable molecule, while the current agents of this type, such as cyclophosphamide and melphalan, have been modified by conjugation with electronegative groups that reduce their reactivity. The single strand adducts are repaired by nucleotide excision repair, while double strand breaks require the complex homologous recombination system. The newest agent of this class, bendamustine (Figure 5-1), consists of a purine-like ring, to which is attached a classical bifunctional nitrogen mustard. This bulky molecule forms adducts that are more slowly repaired. The drug is incompletely cross-resistant with traditional alkylators and is highly effective for chronic lymphocytic leukemia and follicular lymphomas (2).


Molecular structures of melphalan, chlorambucil, cyclophosphamide, ifosfamide, and bendamustine.


Nitrogen mustard undergoes spontaneous chemical rearrangement in aqueous solution to form a highly reactive, positively charged, three-member aziridinium ring, which reacts with nucleophilic sites on DNA such as amines and hydroxyl groups. (R1NH2 and R2NH2 represent reactive sites on DNA bases.)

The second group consists of drugs that transfer single methyl radicals to DNA. This second class—which includes procarbazine, dimethyl triazinoimidazolecarboxamide (DTIC); its close congener, temozolomide; and busulfan—requires more complex activation, either enzymatic or chemical. The methylating drugs preferentially attack the O-6 position of guanine, as well as other reactive sites on purines and pyrimidines. The methylation ...

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