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

Cyclophosphamide
O
1-triazeno)-imidazole-4-carboxamide, usually referred to as dacarbazine
or DTIC, is prototypical of methylating agents.
1679
M
O CH 2
P CH 2
NH
O
hepatic CYPs
CH 2
M =
(ClCH 2 CH 2 ) 2 N
O
M
O
P
CH 2
CH 2
NH CH
OH
4-Hydroxycyclophosphamide Aldophosphamide
aldehyde
enzymatic
dehydrogenase nonenzymatic
O
O
M P
NH
CH 2
CH 2
C
O
O
O CH 2
M P CH 2
NH 2 COOH
Carboxyphosphamide
INACTIVE METABOLITES
M
4-Ketocyclophosphamide
Phosphoramide
mustard
Figure 61–3. Metabolism of cyclophosphamide.
O
P
CH 2
CH 2
NH 2 CHO
O
O –
M P H 2C CH CHO
NH 2
Acrolein
TOXIC METABOLITES
Dacarbazine requires initial activation by hepatic CYPs
through an N-demethylation reaction. In the target cell, spontaneous
cleavage of the metabolite, methyl-triazeno-imidazole-carboxamide
(MTIC), yields an alkylating moiety, a methyl diazonium ion. A
related triazene, temozolomide, undergoes spontaneous, nonenzymatic
activation to MTIC and has significant activity against
gliomas.
N
N
CHAPTER 61
CYTOTOXIC AGENTS
ifosfamide is on the cyclic phosphoramide nitrogen of the oxazaphosphorine
ring. Ifosfamide is activated in the liver by CYP3A4. The
activation of ifosfamide proceeds more slowly, with greater production
of dechlorinated metabolites and chloroacetaldehyde. These differences
in metabolism likely account for the higher doses of
ifosfamide required for equitoxic effects, the greater neurotoxicity of
ifosfamide, and the possible differences in antitumor spectrum of the
two agents.
The newest approved alkylating agent, bendamustine, has
the typical chloroethyl reactive groups attached to a benzimidazole
backbone.
The nitrosoureas, which include compounds such as 1,3-bis-(2-
chloroethyl)-1-nitrosourea (carmustine; BCNU), 1-(2-chloroethyl)-3-
cyclohexyl-1-nitrosourea (lomustine; CCNU), and its methyl
derivative (semustine; methyl-CCNU), as well as the antibiotic streptozocin
(streptozotocin), exert their cytotoxicity through the spontaneous
breakdown to an alkylating intermediate, the 2-chloroethyl
diazonium ion.
Cl
N
Cl
The unique properties and activity of this drug may derive
from this purine-like structure; the agent produces slowly repaired
DNA cross-links, lacks cross-resistance with other classical alkylators
(Leoni et al., 2008), and has significant activity in chronic lymphocytic
leukemia (CLL) and large-cell lymphomas refractory to
standard alkylators.
A unique class of alkylating agents transfers methyl rather
than ethyl groups to DNA. The triazene derivative 5-(3,3-dimethyl-
N
N
CH 3
BENDAMUSTINE
O
OH
The 2-chloroethyl diazonium ion, a strong electrophile, can
alkylate guanine, cytidine, and adenine bases (Ludlum, 1990).
Displacement of the halogen atom can then lead to interstrand or
intrastrand cross-linking of DNA. The formation of cross-links after
the initial alkylation reaction proceeds relatively slowly and can be
reversed by the DNA repair enzyme O 6 -alkyl, methyl guanine
methyltransferase (MGMT), which displaces the chloroethyl adduct
from its binding to guanine in a suicide reaction. The same enzyme,
when expressed in human gliomas, produces resistance to
nitrosoureas and to other methylating agents, including DTIC, temozolomide,
and procarbazine. As with the nitrogen mustards, interstrand
cross-linking appears to be the primary lesion responsible for
the cytotoxicity of nitrosoureas (Ludlum, 1990). The reactions of the
nitrosoureas with macromolecules are shown in Figure 61–4.