Biomedical Engineering Reference
In-Depth Information
In the third generation analogues of cisplatin, “oxaliplatin” [(diaminocyclohexane) oxalato-
platinum(II); cf. Figure 10.11B] and “satraplatin” [bis(aceto)amminedichloro-(cyclohexylamine)
platinum(IV)] all ligands have been replaced by more bulky ligands. They are effective in cells that
show resistance to cisplatin. The unique feature of satraplatin is that platinum is present in the +4
oxidation state (compared to the more cytotoxic +2 oxidation state in the remaining platinum anti-
cancer drugs). As a consequence it will undergo fewer reactions en route that make the drug suitable
as an oral agent, which will potentially improve the quality of life millions of cancer patients.
Presumably, platinum agents mainly cross the cell membranes as uncharged molecules by
passive diffusion, but studies indicate that active transport via Cu transporters are also involved.
Once inside the cell, the compounds hydrolyze, i.e.,
cis
- and carboplatin form the same positively
charged di-aqua species [Pt(NH
3
)
2
(H
2
O)
2
]
2+
. This ligand exchange is essential as the aquated and
positively charged molecules are very reactive toward nucleophilic centers in biomolecules. Thus,
the aqua-platinum complex favors binding to the N7 atoms of the imidazole rings of guanosine (G)
(Figure 10.12) and adenosine (A). Three different types of purine base adducts can be formed in
DNA, all involving coordination to G: monadducts d(Gp), intrastrand crosslinks (1,2-d(GpG),
1,2-d(GpA), 1,3-d(GpXpGp)), and interstrand crosslinks like d(GpG). Platinum crosslinks cause
bending of the double helix of DNA and thus induce changes in the secondary structure of DNA.
Oxaliplatin, with its bulky and hydrophobic ligand causes a larger bend than
cis
- and carboplatin.
In almost all cases of pt-DNA binding, the metal alone cannot be held responsible for binding and
stability, but hydrogen bonding between the ligand and DNA is an additional factor, thus making
the pt drugs “active complexes.”
It is generally assumed that the cytotoxicity of platinum compounds is due to the ability of the
cross-links to block DNA replication and/or prevent transcription, as polymerase enzymes cannot
pass the lesions. The 1,2-intrastrand crosslink may be responsible for the cytotoxicity of cisplatin.
In the
trans
-isomer, this crosslink cannot be established in line with the smaller cytotoxicity of this
complex. Additionally, high mobility group (HMG) proteins recognize and bind to DNA at the
1,2-intrastrand crosslink. The HMG binding prevents the NER system (nucleotide excision repair
system, which normally removes impaired DNA sequences) in removing the platinum adducts.
FIGURE 10.12
Platinum complex with DNA. Platinum (blue) is seen coordinated to two neighboring
guanosine molecules in the DNA string. Nitrogen is blue, oxygen red, and phosphorus orange. The coordinates
are taken from the Protein Data Bank (1A84).
