24.03.1 Alkylating Agents

Alkylating agents exert their cytotoxic effects through the transfer of their alkyl groups to a variety of cellular targets, the most notable being the nitrogenous bases of DNA, particularly the N7 position of guanine. These covalent additions result in either miscoding of the DNA or strand breakage. Although alkylating agents do not distinguish between proliferating and resting cells, they are most toxic for rapidly dividing cells. These agents are most effective when used in combination with other anticancer agents to treat a variety of lymphatic and solid tumours, however, alkylating agents have been shown to be mutagenic and carcinogenic and treatment with these drugs can lead to a second cancer such as leukaemia. In general, the alkylating agents form into two groups, the nitrogen mustard agents and the nitrosureas although others do exist.

The nitrogen mustard group of anticancer agents, typified by cyclophosphamide and the structurally related ifosfamide, are similar to mustard gas, a chemical warfare agent deployed in the First World War. Both drugs share most of the same toxicities and can be considered as prodrugs since they are normally taken orally and become active (and therefore cytotoxic) only after generation of their alkylating species, which are produced by hydroxylation in the liver by cytochrome P450. The hydroxylated intermediates undergo breakdown to form the active ingredients, acrolein and phosphoramide mustard, which interact with DNA to destroy the malignant cells. Cyclophosphamide is particularly useful in the treatment of Hodgkin’s lymphoma, various leukaemias, adenocarcinoma of the ovary and retinoblastoma whilst ifosfamide is used to treat germ cell tumours, ovarian, cervical and breast cancers. The most common adverse effects of both drugs (after nausea, vomiting, diarrhoea and alopecia) are bone marrow depression and haemhorragic cystitis which can lead to fibrosis of the bladder. Secondary malignancies may appear years after initial treatment with these drugs.

The second group of alkylating agents, the nitrosureas, includes the closely related carmustine and lomustine. Both of these agents have the ability to penetrate into the central nervous system and, as such, are particularly useful in the treatment of brain cancers. They work in a similar way to the nitrogen mustards and exert their cytotoxic effects through alkylation of DNA bases that results in DNA strand cross-linking that inhibits DNA replication and eventually RNA and protein synthesis. Apart from the usual adverse effects (alopecia, nausea, vomiting, stomatitis), these agents have been demonstrated to cause myelosuppression, leukopaenia, thrombocytopaenia as well as liver, kidney and lung damage.