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

1688 platinum complexes do not form carbonium ion intermediates
like other alkylating agents or formally alkylate
DNA, they covalently bind to nucleophilic sites on
DNA and share many pharmacological attributes with
alkylators.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Chemistry. Cisplatin and carboplatin are divalent, inorganic, watersoluble,
platinum-containing complexes. Oxaliplatin, a tetravalent
complex, does not display cross-resistance to the divalent compounds
in some experimental tumors. The coordination of di- or
tetravalent platinum with various organic adducts reduces its renal
toxicity and stabilizes the metal ion, as compared to the inorganic
divalent platinum ion.
Mechanism of Action. Cisplatin, carboplatin, and oxaliplatin
enter cells by an active Cu 2+ transporter, CTR1,
and in doing so rapidly degrade the transporter (Kruh,
2003). The compounds are actively extruded from cells
by ATP7A and ATP7B copper transporters and by multidrug
resistance protein 1 (MRP 1); variable expression
of these transporters may contribute to clinical
resistance (Dolan and Fitch, 2007). Inside the cell, the
chloride, cyclohexane, or oxalate ligands of the three
analogs are displaced by water molecules, yielding a
positively charged and highly reactive molecule. In the
primary cytotoxic reaction, the aquated species of the
drug then reacts with nucleophilic sites on DNA and
proteins.
Aquation of cisplatin is favored at the low concentrations of
chloride inside the cell and in the urine. High concentrations of chloride
stabilize the drug, explaining the effectiveness of chloride diuresis
in preventing nephrotoxicity (see “Clinical Toxicities”). The
activated platinum complexes can react with electron-rich molecules,
such as sulfhydryls, and with various sites on DNA, forming both
intrastrand and interstrand cross-links. The N-7 of guanine is a particularly
reactive site, leading to platinum cross-links between adjacent
guanines (GG intrastrand cross-links) on the same DNA strand;
guanine–adenine cross-links also form and may contribute to cytotoxicity.
Interstrand cross-links form less frequently. DNA-platinum
adducts inhibit replication and transcription, lead to single- and
double-stranded breaks and miscoding, and if recognized by p53 and
other checkpoint proteins, cause induction of apoptosis. Although
no quantitative relationship between platinum-DNA adduct formation
and efficacy has been documented, the ability of patients to form
and sustain platinum adducts appears to be an important predictor of
clinical response (Reed et al., 1988). The analogs differ in the conformation
of their adducts and the effects of adduct on DNA structure
and function. Oxaliplatin and carboplatin are slower to form
adducts. The oxaliplatin adducts are bulkier and less readily repaired,
create a different pattern of distortion of the DNA helix, and differ
from cisplatin adducts in the pattern of hydrogen bonding to adjacent
segments of DNA (Sharma et al., 2007).
Unlike the other platinum analogs, oxaliplatin exhibits a cytotoxicity
that does not depend on an active MMR system, which may
explain its greater activity in colorectal cancer. It also seems less
dependent on the presence of high mobility group (HMG) proteins
that are required by the other platinum derivatives. Testicular cancers
have a high concentration of HMG proteins and are quite sensitive
to cisplatin. Basal-type breast cancers, such as those with BRCA1 and
BRCA2 mutations, lack Her 2 amplification and hormone-receptor
expression and appear to be uniquely susceptible to cisplatin
through their upregulation of apoptotic pathways governed by p63
and p73 (Deyoung and Ellisen, 2007). The specificity of cisplatin
with regard to phase of the cell cycle differs among cell types,
although the effects of cross-linking are most pronounced during
the S phase.
The platinum analogs are mutagenic, teratogenic, and carcinogenic.
Cisplatin- or carboplatin-based chemotherapy for ovarian
cancer is associated with a 4-fold increased risk of developing
secondary leukemia.
Resistance to Platinum Analogs. Resistance to the platinum analogs
likely is multifactorial, and the compounds differ in their degree
of cross-resistance. Carboplatin shares cross-resistance with cisplatin
in most experimental tumors, while oxaliplatin does not. A
number of factors influence sensitivity to platinum analogs in
experimental cells, including intracellular drug accumulation, as
determined by the uptake and efflux transporters; intracellular levels
of glutathione and other sulfhydryls such as metallothionein
that bind to and inactivate the drug (Meijer et al., 1990); and rates
of repair of DNA adducts. Repair of platinum-DNA adducts
requires participation of the NER pathway. Inhibition or loss of
NER increases sensitivity to cisplatin in ovarian cancer patients,
while overexpression of NER components is associated with poor
response to cisplatin or oxaliplatin-based therapy in lung, colon,
and gastric cancer (Paré et al., 2008). Higher levels of expression
of the NER component, ERCC1, in tumor cells and peripheral
white blood cells are associated with a lower response rate in
patients with solid tumors (Dolan and Fitch, 2007).
Resistance to cisplatin, but not oxaliplatin, appears to be
partly mediated through loss of function in the MMR proteins
(hMLH1, hMLH2, or hMSH6), which recognize platinum-DNA
adducts and initiate apoptosis.
In the absence of effective repair of DNA-platinum adducts,
sensitive cells cannot replicate or transcribe affected portions of the
DNA strand. However, it is clear that some DNA polymerases can
bypass adducts, especially those created by cisplatin. Oxaliplatin
adducts are less easily bypassed. It remains unproven whether these
polymerases contribute to resistance. Cisplatin resistance related to
loss of active uptake has been demonstrated in yeast; overexpression
of copper efflux transporters, ATP7A and ATP7B, correlates with poor
survival after cisplatin-based therapy for ovarian cancer (Kruh, 2003).