Chemistry Reference
In-Depth Information
been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin. Evidence
also suggests that the two copper efflux transporters ATP7A and ATP7B regulate the efflux of cisplatin. The
precise role that copper transport proteins play in mediating cisplatin resistance remains enigmatic. The
concentration of chloride ions in blood and extracellular body fluids is 100 mM, which is high enough to suppress
cisplatin hydrolysis. Once inside the cell, the concentration of chloride ions is much lower (4 mM), resulting in the
hydrolysis of the drug to form the mono-aqua [PtCl(H
2
O)(NH
3
)
2
]
þ
cation, and more slowly the di-aquo
[Pt(H
2
O)
2
(NH
3
)
2
]
2
þ
(
Figure 22.6
)
. These positively charged species then cross the nuclear membrane and bind to
FIGURE 22.6
Mechanism of the anti-tumour activity of cisplatin.
(From
Brabec & Kasparkova, 2005
.
)
DNA, although they can also bind to RNA and to sulfydryl groups in proteins. Bifunctional cisplatin binds to
DNA, first forming monofunctional adducts, preferentially at guanine residues, which subsequently form major
intrastrand cross-links between adjacent purine residues. In all adducts, the cisplatin is coordinated to the N7 atom
of the purine. These cross-links inhibit DNA replication, block transcription, and ultimately trigger programmed
cell death (apoptosis). The success of cisplatin in cancer chemotherapy derives from its ability to cross-link DNA
and alter the structure. Most cisplatin
DNA adducts are intrastrand d(GpG) and d(ApG) cross-links, which
unwind and bend the duplex to facilitate the binding of proteins that contain one or more high-mobility group
(HMG) domains. When HMG-domain proteins bind cisplatin intrastrand cross-links, they are diverted away from
their natural binding sites on the DNA and shield the adducts from excision repair. This sensitises the cells to
cisplatin and contributes to its cytotoxicity. The X-ray structure of the adduct of Pt(II) with the single-stranded
e
