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

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SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
A
H 3C
B
δ+ δ-
CH 2 CH 2 Cl
C
CH 2 CH 2 Cl
H 3C
Activation
H 3C
CH 2
CH 2
Nucleophilic attack of
unstable aziridine ring by electron donor
(–SH of protein, –N– of protein or DNA base,
=O of DNA base or phosphate)
CH 2 CH 2 Cl
N
+
DNA O CH 2
O
O
DNA
CH 2
CH 2
O
N N
N N NH 2
CH 2 CH 2 Cl
H 3C N
CH 2 CH 2 O
N N
DNA O CH 2
N N NH 2
O
O
DNA
reaction and alkylate a second guanine residue or another nucleophilic
moiety, resulting in the cross-linking of two nucleic acid
chains or the linking of a nucleic acid to a protein, alterations that
would cause a major disruption in nucleic acid function. Any of these
effects could contribute to both the mutagenic and cytotoxic effects
of alkylating agents. The extreme cytotoxicity of bifunctional alkylators
correlates very closely with interstrand cross-linkage of DNA
(Garcia et al., 1988).
The ultimate cause of cell death related to DNA damage is
not known. Specific cellular responses include cell-cycle arrest and
attempts to repair DNA. The specific repair enzyme complex utilized
will depend on two factors: the chemistry of the adduct
formed and the repair capacity of the cell involved. The process of
+
N
CH 2 CH 2 Cl
Figure 61–1. Mechanism of action of alkylating agents.
A. Activation reaction. B. Alkylation of N7 of guanine.
Cl
recognizing and repairing DNA generally requires an intact
nucleotide excision repair (NER) complex, but, as discussed in the
rest of this section, may differ with each drug and with each tumor.
Alternatively, recognition of extensively damaged DNA by p53 can
trigger apoptosis. Mutations of p53 lead to alkylating agent resistance
(Kastan, 1999).
Structure-Activity Relationships. Although these alkylating agents
share the capacity to alkylate biologically important molecules,
modification of the basic chloroethylamino structure changes reactivity,
lipophilicity, active transport across biological membranes,
sites of macromolecular attack, and mechanisms of DNA repair, all
of which properties determine drug activity in vivo. With several of
the most valuable agents (e.g., cyclophosphamide, ifosfamide), the
active alkylating moieties are generated in vivo through hepatic
metabolism.
The biological activity of alkylators of the nitrogen mustard
type is based on the presence of the bis-(2-chloroethyl) group.
Although mechlorethamine has been widely used in the past, linkage
of the bis-(2-chloroethyl) group to election-rich substitutions
such as unsaturated ring systems has yielded more stable drugs with
better pharmacodynamic properties and with greater selective
killing of tumor cells. Bis-(2-chloroethyl) groups linked to amino
acids (phenylalanine) and substituted phenyl groups (aminophenol
butyric acid, as in chlorambucil) create a more stable and orally
available form. The structures of important nitrogen mustards are
shown in Figure 61–2.
A classical example of the role of host metabolism in the
activation and degradation of an alkylating agent is seen with
cyclophosphamide, now the most widely used agent of this class.
The drug undergoes metabolic activation (hydroxylation) by
CYP2B (Figure 61–3), with subsequent transport of the activated
intermediate to sites of action. The selectivity of cyclophosphamide
against certain malignant tissues may result in part from
the capacity of normal tissues to degrade the activated intermediates
via aldehyde dehydrogenase, glutathione transferase, and
other pathways.
Ifosfamide is an oxazaphosphorine, similar to cyclophosphamide.
Cyclophosphamide has two chloroethyl groups on the exocyclic
nitrogen atom, whereas one of the 2-chloroethyl groups of
O O
CH
O O
CH 2 CH P
2 CH 2 Cl
2 Cl
N
P
H 3 C N
NH
N
NHCH 2 CH 2 Cl
CH 2 CH 2 Cl
CH 2 CH 2 Cl
CH 2 CH 2 Cl
MECHLORETHAMINE
CYCLOPHOSPHAMIDE
IFOSFAMIDE
CH 2 CH 2 Cl
CH 2 CH 2 Cl
HOOC CH CH 2 N
HOOC CH 2 CH 2 CH 2 N
CH
NH 2 CH 2 Cl
CH 2 CH 2 Cl
2
MELPHALAN
CHLORAMBUCIL
Figure 61–2. Nitrogen mustards employed in therapy.