DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Cytotoxic Agents
Bruce A. Chabner, Joseph Bertino, James Cleary,
Taylor Ortiz, Andrew Lane, Jeffrey G. Supko,
and David Ryan
I. Alkylating Agents and
Platinum Coordination
Complexes
The pervasive toxic effects of sulfur mustard gas were
noted as the result of its use in World War I. A potent
vesicant, the gas caused a topical burn to skin, eyes,
lungs, and mucosa and, after massive exposure, aplasia
of the bone marrow and lymphoid tissue and ulceration
of the GI tract. Early clinical experiments with
topically applied sulfur mustard led to regression of
penile tumors. Thereafter, Goodman, Gilman, the
originators of this text, working with colleagues at Yale
in a consortium organized by the U.S. Department of
Defense, confirmed the antineoplastic action of the
nitrogen mustards against a murine lymphoma. In
1942, they began clinical studies of intravenous nitrogen
mustards in patients with lymphoma, launching
the modern era of cancer chemotherapy (Gilman and
Philips, 1946).
At present, six major types of alkylating agents
are used in the chemotherapy of neoplastic diseases:
• nitrogen mustards
• ethyleneimines
• alkyl sulfonates
• nitrosoureas
• the triazenes
• DNA-methylating drugs, including procarbazine,
temozolomide, and dacarbazine
In addition, because of similarities in their mechanisms
of action and resistance, platinum complexes
are discussed with classical alkylating agents, even
though they do not alkylate DNA but instead form
covalent metal adducts with DNA. The mechanism of
action of alkylating agents is shown in Figure 61–1.
Chemistry. The chemotherapeutic alkylating agents have in common
the property of forming highly reactive carbonium ion intermediates.
These reactive intermediates covalently link to sites of
high electron density, such as phosphates, amines, sulfhydryl, and
hydroxyl groups. Their chemotherapeutic and cytotoxic effects
are directly related to the alkylation of reactive amines, oxygens,
or phosphates on DNA. The N7 atom of guanine is particularly
susceptible to the formation of a covalent bond with bifunctional
alkylating agents and may represent the key target that determines
their biological effects. Other atoms in the purine and pyrimidine
bases of DNA, including N1 and N3 of the adenine ring, N3 of
cytosine, and O6 of guanine, react with these agents, as do the
amino and sulfhydryl groups of proteins and the sulfhydryls of
glutathione.
The possible actions of alkylating agents on DNA are illustrated
in Figure 61–1 with mechlorethamine (nitrogen mustard).
First, one 2-chloroethyl side chain undergoes a first-order (S N
1)
intramolecular cyclization, with release of Cl − and formation of a
highly reactive ethyleneimine intermediate (Figure 61–1). The
unstable quaternary amine then reacts with a variety of electrondense
sites. This latter reaction proceeds as a second-order (S N
2)
nucleophilic substitution. Alkylation of the N7 of guanine in DNA,
a highly favored reaction, exerts several biologically important
effects. Guanine residues in DNA exist predominantly as the keto
tautomer and readily make Watson-Crick base pairs by hydrogen
bonding with cytosine residues. However, when the N7 of guanine
is alkylated (to become a quaternary ammonium nitrogen) the guanine
residue is more acidic and the enol tautomer is favored. The
modified guanine can mispair with thymine residues during DNA
synthesis, leading to the substitution of thymine for cytosine.
Second, alkylation of the N7 creates lability in the imidazole ring,
leading to opening of the ring and excision of the damaged guanine
residue. Mispairing and imidazole ring opening can lead to attempts
to repair the damaged stretch of DNA, causing strand breakage.
Third, with bifunctional alkylating agents such as nitrogen mustard,
the second 2-chloroethyl side chain can undergo a similar cyclization