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

1680
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
CIH 2 CH 2 C
CIH 2 CH 2 C
O
N C
N O
N NOH O C N
Because the formation of the ethyleneimine ion constitutes
the initial reaction of the nitrogen mustards, it is not surprising that
stable ethyleneimine derivatives have antitumor activity. Several
compounds of this type, including triethylenemelamine (TEM) and
triethylenethiophosphoramide (thiotepa), have been used clinically.
In standard doses, thiotepa produces little toxicity other than myelosuppression;
it also is used for high-dose chemotherapy regimens, in
which it causes both mucosal and central nervous system toxicity.
Altretamine (hexamethylmelamine; HMM) is mentioned here
because of its chemical similarity to TEM. The methylmelamines
are N-demethylated by hepatic microsomes with the release of
formaldehyde, and there is a direct relationship between the degree
of the demethylation and their activity against murine tumors.
Esters of alkane sulfonic acids alkylate DNA through the
release of methyl radicals. Busulfan is of value in high-dose
chemotherapy.
Pharmacological Actions
CH 2 CH 2 Cl
CH 2 CH 2 Cl
+
CICH 2 CH 2 N 2
–
OH
Alkylation of
Guanine
O
of DNA
ε-NH
CH 2 CH 2 Cl
2 -Lysine
of Protein
N
N
H 2 N N N
DNA O CH 2
O
O
PROTEIN NH C NH CH 2 CH 2 Cl
O DNA
Alkylated DNA
Carbamoylated Protein
Figure 61–4. Degradation of carmustine (BCNU) with generation
of alkylating and carbamylating intermediates.
Cytotoxic Actions. The capacity of alkylating agents to
interfere with DNA integrity and function and to induce
cell death in rapidly proliferating tissues provides the
basis for their therapeutic and toxic properties. Acute
effects manifest primarily against rapidly proliferating
tissues; however, certain alkylating agents may have
damaging effects on tissues with normally low mitotic
indices (e.g., liver, kidney, and mature lymphocytes),
NH
which usually are affected in a delayed time frame.
Lethality of DNA alkylation depends on the recognition
of the adduct, the creation of DNA strand breaks by
repair enzymes, and an intact apoptotic response. The
actual mechanism(s) of cell death related to DNA alkylation
are not yet well characterized.
In non-dividing cells, DNA damage activates a checkpoint
that depends on the presence of a normal p53 gene. Cells thus
blocked in the G 1
/S interface either repair DNA alkylation or
undergo apoptosis. Malignant cells with mutant or absent p53 fail
to suspend cell-cycle progression, do not undergo apoptosis, and
exhibit resistance to these drugs.
Although DNA is the ultimate target of all alkylating agents,
a crucial distinction must be made between the bifunctional agents,
in which cytotoxic effects predominate, and the monofunctional
methylating agents (procarbazine, temozolomide), which have
greater capacity for mutagenesis and carcinogenesis. This suggests
that the cross-linking of DNA strands represents a much greater
threat to cellular survival than do other effects, such as single-base
alkylation and the resulting depurination and single-chain scission.
On the other hand, simple methylation may be bypassed by DNA
polymerases, leading to mispairing reactions that permanently
modify DNA sequence. These new sequences are transmitted to
subsequent generations and may result in mutagenesis or carcinogenesis.
Some methylating agents, such as procarbazine, are highly
carcinogenic.
DNA repair systems play an important role in removing
adducts, and thereby determine the selectivity of action against particular
cell types, and acquired resistance to alkylating agents.
Alkylation of a single strand of DNA (mono-adducts) is repaired by
the nucleotide excision repair pathway, while the less frequent crosslinks
require participation of nonhomologous end joining, an errorprone
pathway, or the error-free homologous recombination
pathway. After drug infusion in humans, mono-adducts appear rapidly
and peak within 2 hours of drug exposure, while cross-links
peak at 8 hours. The t 1/2
for repair of adducts varies among normal
tissues and tumors; in peripheral blood mononuclear cells, both
mono-adducts and cross-links disappear with a t 1/2
of 12-16 hours
(Souliotis et al., 1990).
The homologous end-joining pathway has multiple components
(Wang et al., 2001):
• sensors of DNA integrity (such as p53)
• activation signals such as the ataxia-telangiectasia-mutated
(ATM) and ataxia-telangiectasia and rad-related (ATR) proteins
• the activated repair complex composed of Fanconi anemia proteins
and BRCA2, all of which localize at the site of DNA damage
and initiate removal of the cross-linked segment of DNA
• homologous recombination, which allows resynthesis of the
damaged DNA sequence followed by re-ligation of the repaired
sequences
The process depends on the presence and accurate functioning of
multiple proteins. Their absence or mutation, as in Fanconi anemia
or ataxia telangiectasia, leads to extreme sensitivity to DNA
cross-linking agents such as mitomycin, cisplatin, or classical
alkylators.