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The major clinically useful alkylating agents have a structure containing a bis(chloroethyl)amine, ethyleneimine, or nitrosourea moiety. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful.
Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity.
and busulfan are used for specialized purposes for ovarian cancer and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU).
a class, the alkylating agents exert their cytotoxic effects via the
transfer of their alkyl groups to various cellular constituents.
Alkylations of DNA within the nucleus probably represent the major
interactions that lead to cell death. However, these drugs react
chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate
groups of other cellular nucleophiles as well.
mechanism of action of these drugs involves intramolecular cyclization
to form an ethyleneimonium ion that may directly or through the
formation of a carbonium ion transfer an alkyl group to a cellular
constituent. In addition to alkylation, a secondary mechanism that
occurs with nitrosoureas involves carbamoylation of lysine residues of
proteins through the formation of isocyanates.
agents have direct vesicant effects and can damage tissues at the site
of injection as well as produce systemic toxicity. Toxicities are
generally dose-related and occur particularly in rapidly growing tissues
such as bone marrow, the gastrointestinal tract, and the reproductive
After intravenous injection, nausea and vomiting
usually occur within 30–60 minutes with mechlorethamine,
cyclophosphamide, or carmustine. The emetogenic effects are mediated by
the central nervous system and can be reduced by pretreatment with 5-HT3
(serotonin) receptor antagonists such as ondansetron or granisetron.
Cyclophosphamide is inactive in its parent form and must be activated to cytotoxic forms by liver microsomal enzymes. The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.
of alkylating agents has been of great clinical value.
Cyclophosphamide, melphalan, chlorambucil, busulfan, and, more recently,
temozolomide are those most commonly given via the oral route, and
their cytotoxic effects are similar to those observed with parenteral
In general, if a tumor is resistant to one
alkylating agent, it will be relatively resistant to other agents of
this class (though not necessarily to nitrosoureas); however, there are
exceptions to this rule depending on the specific tumor.
is the most widely used alkylating agent. The oral drug busulfan has a
major degree of specificity for the granulocyte series and is therefore
of particular value in the treatment of chronic myelogenous leukemia.
all oral alkylating agents, some degree of leukopenia is necessary to
provide evidence that the drug has been absorbed adequately. Frequent
monitoring of blood counts is essential during the administration of
these agents as the development of severe leukopenia or thrombocytopenia
necessitates immediate interruption of therapy.
drugs appear to be non-cross-resistant with other alkylating agents;
all require biotransformation, which occurs by nonenzymatic
decomposition, to metabolites with both alkylating and carbamoylating
Although the majority of alkylations by the
nitrosoureas are on the N7 position of guanine in DNA, the critical
alkylation responsible for cytotoxicity is on the O6 of guanine, which
leads to G-C crosslinks in DNA.
After oral administration of
lomustine, peak plasma levels of metabolites appear within 1–4 hours;
central nervous system concentrations reach 30–40% of the activity
present in the plasma. While the initial plasma half-life is
approximately 6 hours, a second half-life is 1–2 days.
Urinary excretion appears to be the major route of elimination from the body.
naturally occurring sugar-containing nitrosourea, streptozocin, is
interesting because it has minimal bone marrow toxicity. This agent has
activity in the treatment of insulin-secreting islet cell carcinoma of
variety of other compounds have mechanisms of action that involve
alkylation. These include procarbazine, dacarbazine, altretamine
(hexamethylmelamine), cisplatin, and carboplatin.
oral agent procarbazine is a methylhydrazine derivative, and it is
commonly used in combination regimens for Hodgkin's disease,
non-Hodgkin's lymphoma, and brain tumors. This drug has leukemogenic,
teratogenic, and mutagenic properties.
The precise mechanism
of action of procarbazine is uncertain; however, the drug inhibits DNA,
RNA, and protein biosynthesis; prolongs interphase; and produces
There is an increased risk of secondary
cancers in the form of acute leukemia, and the carcinogenic potential of
procarbazine is thought to be higher than that of most other alkylating
Dacarbazine is a
synthetic compound that functions as an alkylating agent following
metabolic activation by liver microsomal enzymes by oxidative
N-demethylation to the monomethyl derivative. This metabolite
spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is
excreted in the urine, and diazomethane. The diazomethane generates a
methyl carbonium ion that is believed to be the cytotoxic species.
is administered parenterally and is not schedule-dependent. It produces
marked nausea, vomiting, and myelosuppression. Its major applications
are in melanoma, Hodgkin's disease, and soft tissue sarcomas.
(Hexamethylmelamine) is structurally similar to triethylenemelamine. It
is relatively insoluble and available only in oral form. It is rapidly
biotransformed in the liver by demethylation to the pentamethylmelamine
and tetramethylmelamine metabolites.
This agent is approved
for use in ovarian cancer patients who have progressed despite treatment
with a regimen based on platinum or an alkylating agent (or both).
The main dose-limiting toxicities include nausea, vomiting, and myelosuppression. Neurotoxicity in the form of somnolence, mood changes, and peripheral neuropathy is also observed.